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Sample records for early antiviral therapy

  1. Antiviral therapy: a perspective.

    PubMed

    Shahidi Bonjar, Amir Hashem

    2016-01-01

    research has yielded positive results in animal models, EVAC could be used as a supportive treatment in humans along with conventional antiviral therapies. EVAC would not be suitable for all viral infections, but could be expected to decrease the casualties resulting from blood-borne viral infections. The EVAC approach would be efficient in terms of time, effort, and expenditure in the research and treatment of blood-borne viral infections.

  2. Antiviral therapy: current concepts and practices.

    PubMed Central

    Bean, B

    1992-01-01

    Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future. PMID:1576586

  3. Humanized Antibodies for Antiviral Therapy

    NASA Astrophysics Data System (ADS)

    Co, Man Sung; Deschamps, Marguerite; Whitley, Richard J.; Queen, Cary

    1991-04-01

    Antibody therapy holds great promise for the treatment of cancer, autoimmune disorders, and viral infections. Murine monoclonal antibodies are relatively easy to produce but are severely restricted for therapeutic use by their immunogenicity in humans. Production of human monoclonal antibodies has been problematic. Humanized antibodies can be generated by introducing the six hypervariable regions from the heavy and light chains of a murine antibody into a human framework sequence and combining it with human constant regions. We humanized, with the aid of computer modeling, two murine monoclonal antibodies against herpes simplex virus gB and gD glycoproteins. The binding, virus neutralization, and cell protection results all indicate that both humanized antibodies have retained the binding activities and the biological properties of the murine monoclonal antibodies.

  4. CRM1 Inhibitors for Antiviral Therapy

    PubMed Central

    Mathew, Cynthia; Ghildyal, Reena

    2017-01-01

    Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1) is observed. Overexpression of CRM1-mediated nuclear export is evident in several solid and hematological malignancies. Interestingly, CRM1-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly. This review summarizes the role of CRM1 in cancer and selected viruses. Leptomycin B (LMB) is the prototypical inhibitor of CRM1 potent against various cancer cell lines overexpressing CRM1 and in limiting viral infections at nanomolar concentrations in vitro. However, the irreversible shutdown of nuclear export results in high cytotoxicity and limited efficacy in vivo. This has prompted search for synthetic and natural CRM1 inhibitors that can potentially be developed as broadly active antivirals, some of which are summarized in this review. PMID:28702009

  5. Flavivirus Infection Impairs Peroxisome Biogenesis and Early Antiviral Signaling

    PubMed Central

    You, Jaehwan; Hou, Shangmei; Malik-Soni, Natasha; Xu, Zaikun; Kumar, Anil; Rachubinski, Richard A.; Frappier, Lori

    2015-01-01

    ABSTRACT Flaviviruses are significant human pathogens that have an enormous impact on the global health burden. Currently, there are very few vaccines against or therapeutic treatments for flaviviruses, and our understanding of how these viruses cause disease is limited. Evidence suggests that the capsid proteins of flaviviruses play critical nonstructural roles during infection, and therefore, elucidating how these viral proteins affect cellular signaling pathways could lead to novel targets for antiviral therapy. We used affinity purification to identify host cell proteins that interact with the capsid proteins of West Nile and dengue viruses. One of the cellular proteins that formed a stable complex with flavivirus capsid proteins is the peroxisome biogenesis factor Pex19. Intriguingly, flavivirus infection resulted in a significant loss of peroxisomes, an effect that may be due in part to capsid expression. We posited that capsid protein-mediated sequestration and/or degradation of Pex19 results in loss of peroxisomes, a situation that could result in reduced early antiviral signaling. In support of this hypothesis, we observed that induction of the lambda interferon mRNA in response to a viral RNA mimic was reduced by more than 80%. Together, our findings indicate that inhibition of peroxisome biogenesis may be a novel mechanism by which flaviviruses evade the innate immune system during early stages of infection. IMPORTANCE RNA viruses infect hundreds of millions of people each year, causing significant morbidity and mortality. Chief among these pathogens are the flaviviruses, which include dengue virus and West Nile virus. Despite their medical importance, there are very few prophylactic or therapeutic treatments for these viruses. Moreover, the manner in which they subvert the innate immune response in order to establish infection in mammalian cells is not well understood. Recently, peroxisomes were reported to function in early antiviral signaling, but

  6. Autoimmune disease: A role for new anti-viral therapies?

    PubMed

    Dreyfus, David H

    2011-12-01

    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.

  7. Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.

    PubMed

    Mulhall, Brian P; Younossi, Zobair

    2005-01-01

    Nearly 4 million people in the United States have evidence of hepatitis C infection (HCV), representing a significant cause of cirrhosis and liver cancer as well a major burden to our healthcare systems and society. Antiviral therapy can successfully eradicate HCV over the long term, potentially reducing the risk of progression and improving patients' quality of life. The currently preferred HCV treatment is a combination of pegylated interferon alfa and ribavirin, which can achieve an overall sustained viral eradication rate of 55%. The duration of this treatment is typically determined by HCV genotype and the patient's early virologic response to the antiviral regimen. Evidence has accumulated over the past few years to indicate that close adherence to the optimal antiviral regimen can enhance sustained virologic response. But optimal treatment outcomes require diligence and careful management of side effects related to combination therapy. Although reducing the dose of pegylated interferon alfa, ribavirin, or both can effectively treat side effects, suboptimal doses of this regimen, especially ribavirin, may negatively affect virologic response. An alternative strategy is to use growth factors to treat cytopenias. This strategy can obviate dose reductions while potentially improving patients' quality of life. Patient support seems especially important early after the initiation of antiviral therapy. Encouraging study findings involving the growth factors, epoetin alfa and darbepoetin alfa, suggest improved anemia and quality of life while maintaining the optimal ribavirin dose. Future work should be aimed at providing stronger evidence for the use of these "supportive products" during anti-HCV therapy. As we strive to develop better treatment options for our HCV patients, the importance of adhering to the treatment regimen continues to play a central role. Effective side effect management is crucial for the success of this treatment because adherence is

  8. Evasion of Early Antiviral Responses by Herpes Simplex Viruses

    PubMed Central

    Suazo, Paula A.; Ibañez, Francisco J.; Retamal-Díaz, Angello R.; Paz-Fiblas, Marysol V.; Bueno, Susan M.; Kalergis, Alexis M.; González, Pablo A.

    2015-01-01

    Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs) must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency. PMID:25918478

  9. Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

    NASA Astrophysics Data System (ADS)

    Komarova, Natalia L.; Barnes, Eleanor; Klenerman, Paul; Wodarz, Dominik

    2003-02-01

    Drug therapies against persistent human infections such as hepatitis C virus, hepatitis B virus, and HIV fail to consistently eradicate the infection from the host. Hence, recent emphasis has shifted to the study of antiviral therapy aimed at boosting specific immune responses. It was argued that structured therapy interruptions were required to achieve this, because such regimes have shown promising results in early HIV infection. Using mathematical models, we show that, contrary to this notion, a single phase of drug therapy can result in the establishment of sustained immunity. We present a simple relationship between timing of therapy and efficacy of the drugs required for success. In the presence of strong viral suppression, we show that therapy should be stopped relatively early, and that a longer duration of treatment leads to failure. On the other hand, in the presence of weaker viral suppression, stopping treatment too early is detrimental, and therapy has to be continued beyond a time threshold. We discuss our modeling results primarily in the context of HCV therapy during chronic infection. Although the therapy regimes explored here also have implications for HIV, virus-mediated destruction of specific immune cells renders success unlikely during the chronic phase of the infection.

  10. Towards antiviral therapies for treating dengue virus infections.

    PubMed

    Kaptein, Suzanne Jf; Neyts, Johan

    2016-10-01

    Dengue virus is an emerging human pathogen that poses a huge public health burden by infecting annually about 390 million individuals of which a quarter report with clinical manifestations. Although progress has been made in understanding dengue pathogenesis, a licensed vaccine or antiviral therapy against this virus is still lacking. Treatment of patients is confined to symptomatic alleviation and supportive care. The development of dengue therapeutics thus remains of utmost importance. This review focuses on the few molecules that were evaluated in dengue virus-infected patients: balapiravir, chloroquine, lovastatin, prednisolone and celgosivir. The lessons learned from these clinical trials can be very helpful for the design of future trials for the next generation of dengue virus inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Budesonide and Formoterol Reduce Early Innate Anti-Viral Immune Responses In Vitro

    PubMed Central

    Davies, Janet M.; Carroll, Melanie L.; Li, Hongzhuo; Poh, Alisa M.; Kirkegard, Darren; Towers, Michelle; Upham, John W.

    2011-01-01

    Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance

  12. Spectroscopic investigation of herpes simplex viruses infected cells and their response to antiviral therapy

    NASA Astrophysics Data System (ADS)

    Erukhimovitch, Vitaly; Talyshinsky, Marina; Souprun, Yelena; Huleihel, Mahmoud

    2006-07-01

    In the present study, we used microscopic Fourier transform infrared spectroscopy (FTIR) to evaluate the antiviral activity of known antiviral agents against herpes viruses. The antiviral activity of Caffeic acid phenethyl ester (CAPE) (which is an active compound of propolis) against herpes simplex type 1 and 2 was examined in cell culture. The advantage of microscopic FTIR spectroscopy over conventional FTIR spectroscopy is that it facilitates inspection of restricted regions of cell culture or tissue. Our results showed significant spectral differences at early stages of infection between infected and non-infected cells, and between infected cells treated with the used antiviral agent and those not treated. In infected cells, there was a considerable increase in phosphate levels. Our results show that treatment with used antiviral agent considerably abolish the spectral changes induced by the viral infection. In addition, it is possible to track by FTIR microscopy method the deferential effect of various doses of the drug.

  13. Antiviral therapies for chronic hepatitis C virus infection with cirrhosis

    PubMed Central

    Nakamoto, Shingo; Kanda, Tatsuo; Shirasawa, Hiroshi; Yokosuka, Osamu

    2015-01-01

    Patients who are infected with hepatitis C virus (HCV) and also have advanced fibrosis or cirrhosis have been recognized as “difficult-to-treat” patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents (DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatment-naïve patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in null-responders and in patients with cirrhosis. Interferon-free regimens in combination with ribavirin and

  14. Genome editing and the next generation of antiviral therapy

    PubMed Central

    Stone, Daniel; Niyonzima, Nixon

    2016-01-01

    Engineered endonucleases such as homing endonucleases (HEs), zinc finger nucleases (ZFNs), Tal-effector nucleases (TALENS) and the RNA-guided engineered nucleases (RGENs or CRISPR/Cas9) can target specific DNA sequences for cleavage, and are proving to be valuable tools for gene editing. Recently engineered endonucleases have shown great promise as therapeutics for the treatment of genetic disease and infectious pathogens. In this review, we discuss recent efforts to use the HE, ZFN, TALEN and CRISPR/Cas9 gene-editing platforms as antiviral therapeutics. We also discuss the obstacles facing gene-editing antiviral therapeutics as they are tested in animal models of disease and transition towards human application. PMID:27272125

  15. Antiviral Therapy in Steroid-refractory Ulcerative Colitis with Cytomegalovirus: Systematic Review and Meta-analysis.

    PubMed

    Shukla, Tushar; Singh, Siddharth; Loftus, Edward V; Bruining, David H; McCurdy, Jeffrey D

    2015-11-01

    The role of antiviral therapy in patients with ulcerative colitis (UC) with cytomegalovirus (CMV) remains unclear. We therefore performed a systematic review and meta-analysis to assess the association between antiviral therapy and the risk of colectomy. Multiple electronic databases were searched systematically through July 2014 for studies reporting the risk of colectomy in patients with UC with CMV stratified by treatment with antiviral agents. Colectomy rates were assessed for the overall cohort and stratified by corticosteroid (CS) refractoriness. We estimated summary odds ratios and 95% confidence intervals, using random-effects model, and used Grading of Recommendations Assessment, Development, and Evaluation criteria to appraise the quality of evidence. Fifteen observational studies (333 patients with UC with CMV, 43.2% treated with antiviral agents) were identified, of which 8 stratified patients according to CS-refractory disease (55.4% treated with antiviral agents). Antiviral therapy resulted in a significantly lower risk of colectomy in patients with CS-refractory disease (odds ratio, 0.20; 95% confidence interval, 0.08-0.49; I = 0%) but not in the overall population of patients with UC (odds ratio, 0.92; 95% confidence interval, 0.31-2.76; I = 65). The quality evidence was low. The results were stable when restricting the analysis to patients with a tissue diagnosis of CMV and studies that defined CS-refractory disease as a failure to respond to intravenous CS. Antiviral therapy may benefit a subgroup of patients with UC who are refractory to CS. Further prospective trials are required to confirm these findings.

  16. Community nurse-led initiation of antiviral therapy for chronic hepatitis C in people who inject drugs does not increase uptake of or adherence to treatment.

    PubMed

    Lewis, Heather; Kunkel, Jan; Axten, David; Dalton, Jane; Gardner, Hayley; Tippett, Andrew; Wynne, Stephanie; Wilkinson, Mandie; Foster, Graham R

    2016-11-01

    Chronic hepatitis C is common in people who inject drugs (PWID) and this population serves as a reservoir for infection. Treatment levels are low among this group, ranging from 1 to 19%. We explored whether a nurse-initiated community treatment model increased uptake of and adherence to interferon-based therapies. This was a cluster randomized trial of nurse-initiated versus physician-initiated antiviral therapy with pegylated interferon and ribavirin for hepatitis C virus in community clinics (trial registration: ISRCTN07774040). The proportion of participants initiating treatment during follow-up was 10% with nurse-initiated (6/62) and 9% with physician-initiated (6/76) therapy. Adherence was similar in both groups, with only one patient in each arm not adhering to therapy. There were no serious adverse events, but interferon-related side effects were common. Drug and alcohol use did not change during therapy. Despite easy access to antiviral therapy, uptake of treatment was poor, with no significant difference between the groups. Nurse-led initiation of interferon-based antiviral therapy in PWID did not lead to increased uptake of, response to or adherence with treatment. Further service improvement is unlikely to increase the proportion of PWID undergoing antiviral therapy for hepatitis C virus and early adoption of interferon-free regimens may increase the proportion initiating and completing treatment.

  17. Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model.

    PubMed

    Everts, Maaike; Cihlar, Tomas; Bostwick, J Robert; Whitley, Richard J

    2017-01-06

    Drug discovery and development is a lengthy and expensive process. Although no one, simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure. Together, these steps could result in accelerated timelines for bringing antiviral therapies to market so they can treat emerging infections and reduce human suffering.

  18. Meeting report: 4th ISIRV antiviral group conference: Novel antiviral therapies for influenza and other respiratory viruses.

    PubMed

    McKimm-Breschkin, Jennifer L; Fry, Alicia M

    2016-05-01

    The International Society for Influenza and other Respiratory Virus Diseases (isirv) held its 4th Antiviral Group Conference at the University of Texas on 2-4 June, 2015. With emerging resistance to the drugs currently licensed for treatment and prophylaxis of influenza viruses, primarily the neuraminidase inhibitor oseltamivir phosphate (Tamiflu) and the M2 inhibitors amantadine and rimantadine, and the lack of effective interventions against other respiratory viruses, the 3-day programme focused on the discovery and development of inhibitors of several virus targets and key host cell factors involved in virus replication or mediating the inflammatory response. Virus targets included the influenza haemagglutinin, neuraminidase and M2 proteins, and both the respiratory syncytial virus and influenza polymerases and nucleoproteins. Therapies for rhinoviruses and MERS and SARS coronaviruses were also discussed. With the emerging development of monoclonal antibodies as therapeutics, the potential implications of antibody-dependent enhancement of disease were also addressed. Topics covered all aspects from structural and molecular biology to preclinical and clinical studies. The importance of suitable clinical trial endpoints and regulatory issues were also discussed from the perspectives of both industry and government. This meeting summary provides an overview, not only for the conference participants, but also for those interested in the current status of antivirals for respiratory viruses. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy.

    PubMed

    Saraiya, N; Yopp, A C; Rich, N E; Odewole, M; Parikh, N D; Singal, A G

    2018-05-30

    Although studies suggest decreased incident hepatocellular carcinoma (HCC) after direct-acting antivirals (DAA), data are conflicting regarding HCC recurrence and aggressiveness in patients who have a history of HCC with complete response. Characterize HCC recurrence patterns after DAA therapy. Two reviewers searched MEDLINE and SCOPUS from January 2015 to December 2017 and identified studies evaluating HCC recurrence patterns following DAA therapy. A pooled estimate was calculated using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with PRISMA guidelines. Among 24 studies (n = 1820 patients), the proportion of patients with HCC recurrence following DAA therapy ranged from 0% to 59% (pooled estimate 24.4%; 95% CI: 18.4%-30.4%). Among 11 full text manuscripts, pooled HCC recurrence was 21.9% (95% CI: 16.2%-28.3%). Factors associated with recurrence included history of prior HCC recurrence and a shorter interval between HCC complete response and DAA initiation. Nine studies comparing DAA-treated and interferon-treated or untreated patients found similar recurrence among DAA-treated patients. Most (77.8%) patients with HCC recurrence were detected at an early tumour stage, of whom 64.7% received curative treatment. Study limitations included heterogeneous cohorts, potential misclassification of HCC absence prior to DAA, ascertainment bias for recurrence, and short durations of follow-up. Current data suggest acceptable HCC recurrence rates after DAA therapy, particularly if DAA therapy is delayed at least 6 months after HCC complete response. However, data characterising HCC recurrence after DAA therapy are of limited quality, highlighting the need for high quality prospective studies. © 2018 John Wiley & Sons Ltd.

  20. Drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy.

    PubMed

    Gheorghe, Liana; Cotruta, Bogdan; Trifu, Viorel; Cotruta, Cristina; Becheanu, Gabriel; Gheorghe, Cristian

    2008-09-01

    Pegylated interferon-alpha in combination with ribavirin currently represents the therapeutic standard for the hepatitis C virus infection. Interferon based therapy may be responsible for many cutaneous side effects. We report a case of drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy. To our knowledge, this is the first reported case of Sweet's syndrome in association with pegylated interferon-alpha therapy.

  1. Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade

    PubMed Central

    2013-01-01

    Although much advancement has been achieved in the treatment of chronic hepatitis B, antiviral resistance is still a challenging issue. Previous generation antiviral agents have already developed resistance in a number of patients, and it is still being used especially in resource limited countries. Once antiviral resistance occurs, it predisposes to subsequent resistance, resulting in multidrug resistance. Therefore, prevention of initial antiviral resistance is the most important strategy, and appropriate choice and modification of therapy would be the cornerstone in avoiding treatment failures. Until now, management of antiviral resistance has been evolving from sequential therapy to combination therapy. In the era of tenofovir, the paradigm shifts again, and we have to decide when to switch and when to combine on the basis of newly emerging clinical data. We expect future eradication of chronic hepatitis B virus infection by proper prevention and optimal management of antiviral resistance. PMID:24133659

  2. Dynamics of an HBV Model with Drug Resistance Under Intermittent Antiviral Therapy

    NASA Astrophysics Data System (ADS)

    Zhang, Ben-Gong; Tanaka, Gouhei; Aihara, Kazuyuki; Honda, Masao; Kaneko, Shuichi; Chen, Luonan

    2015-06-01

    This paper studies the dynamics of the hepatitis B virus (HBV) model and the therapy regimens of HBV disease. First, we propose a new mathematical model of HBV with drug resistance, and then analyze its qualitative and dynamical properties. Combining the clinical data and theoretical analysis, we demonstrate that our model is biologically plausible and also computationally viable. Second, we demonstrate that the intermittent antiviral therapy regimen is one of the possible strategies to treat this kind of complex disease. There are two main advantages of this regimen, i.e. it not only may delay the development of drug resistance, but also may reduce the duration of on-treatment time compared with the long-term continuous medication. Moreover, such an intermittent antiviral therapy can reduce the adverse side effects. Our theoretical model and computational results provide qualitative insight into the progression of HBV, and also a possible new therapy for HBV disease.

  3. Modelling Hepatitis B Virus Antiviral Therapy and Drug Resistant Mutant Strains

    NASA Astrophysics Data System (ADS)

    Bernal, Julie; Dix, Trevor; Allison, Lloyd; Bartholomeusz, Angeline; Yuen, Lilly

    Despite the existence of vaccines, the Hepatitis B virus (HBV) is still a serious global health concern. HBV targets liver cells. It has an unusual replication process involving an RNA pre-genome that the reverse transcriptase domain of the viral polymerase protein translates into viral DNA. The reverse transcription process is error prone and together with the high replication rates of the virus, allows the virus to exist as a heterogeneous population of mutants, known as a quasispecies, that can adapt and become resistant to antiviral therapy. This study presents an individual-based model of HBV inside an artificial liver, and associated blood serum, undergoing antiviral therapy. This model aims to provide insights into the evolution of the HBV quasispecies and the individual contribution of HBV mutations in the outcome of therapy.

  4. Effects of Complementary Combination Therapy of Korean Red Ginseng and Antiviral Agents in Chronic Hepatitis B.

    PubMed

    Choi, Seung-Hwa; Yang, Keum-Jin; Lee, Dong-Soo

    2016-12-01

    Chronic hepatitis B management is commonly targeted at reducing viral replication. However, the currently available antiviral therapies are associated with some problems, including resistance and numerous adverse effects. Ginseng has been reported to be effective for treating viral infections such as influenza and human immunodeficiency virus. However, there are currently few studies on the effects of ginseng in chronic hepatitis B. Thus, this study investigated the effects of ginseng together with antiviral agents in chronic hepatitis B. This was a prospective, single-blinded, randomized controlled trial, and single-center study. Thirty-eight patients were enrolled. The control group (n = 19) was administered antiviral agents alone. The experimental group (n = 19) was administered antiviral agents along with Korean Red Ginseng powder capsules (each dose is 1 gram (two capsules), a one-day dose is 3 grams). The baseline characteristics did not differ between the two groups. Differences in several non-invasive fibrosis serologic markers (type IV collagen, hyaluronic acid, transforming growth factor-β) and in the hepatitis B virus DNA levels were compared between the groups. The non-invasive fibrosis serologic markers were further decreased in the experimental group, with significant differences after treatment observed for hyaluronic acid (p = 0.032) and transforming growth factor-β (p = 0.008), but not for type IV collagen (p = 0.174). This study suggests the possibility of Korean Red Ginseng as a complementary therapy for chronic hepatitis B.

  5. [Analysis of the cost-effectiveness of antiviral therapies in chronic hepatitis B patients in Korea].

    PubMed

    Kim, Byung Kook; Kwon, So Young; Lee, Chang Hong; Choe, Won Hyeok; Choi, Hong Mi; Koo, Hye Won

    2009-03-01

    The purpose of this study was to evaluate the cost-effectiveness of 1 year and up to 5 years of antiviral treatment for chronic hepatitis B (CHB). Two ten-health-state Markov models were developed for CHB patients. The proportion of patients remaining alive in each health state, and healthcare costs and quality-adjusted life years (QALYs) were determined during annual cycles of these Markov models. The total healthcare costs, life years, and QALYs over the 40-year time horizon of the model were calculated. The perspectives of the cost-effectiveness analysis were the Korean healthcare system and the healthcare needs of the CHB patient. Short-course therapy with alpha-interferon or 1-year treatment with pegylated interferon alpha-2a, lamivudine (LMV), or adefovir (ADV) had limited impact on disease progression. In contrast, either LMV-ADV or ADV-LMV as rescue medication administered for 5 years resulted in a more sustained decrease in the rate of disease progression. The cost-effectiveness threshold in Korea was estimated to be approximately 25,000,000 South Korean won. LMV administered for 1 year is cost-effective in comparison with no treatment for both HBeAg-positive and HBeAg-negative CHB patients, but longer duration antiviral therapies administered for up to 5 years in CHB patients were found to be highly cost-effective by international standards. Antiviral treatment of CHB with LMV or ADV for up to 5 years using the alternative antiviral agent as rescue medication appears to be a cost-effective strategy for both HBeAg-positive and HBeAg-negative CHB patients in Korea. Economic evaluation of antiviral therapies should be studied further and updated, particularly for newer agents.

  6. Successful Treatment of Corticosteroid with Antiviral Therapy for a Neonatal Liver Failure with Disseminated Herpes Simplex Virus Infection

    PubMed Central

    Maeba, Shinji; Hasegawa, Shunji; Shimomura, Maiko; Ichimura, Takuya; Takahashi, Kazumasa; Motoyama, Masashi; Fukunaga, Shinnosuke; Ito, Yoshinori; Ichiyama, Takashi; Ohga, Shouichi

    2015-01-01

    Background Herpes simplex virus (HSV) infection carries one of the poorest outcomes of neonatal liver failure (NLF). Neonates with disseminated HSV infection can develop hemophagocytic lymphohistiocytosis (HLH), and occasionally need orthotopic liver transplantation. Early interventions may be critical for the cure of NLF. Case Report We describe herewith a 6-day-old neonate with fulminant hepatic failure due to disseminated HSV-1 infection, who successfully responded to high-dose corticosteroid therapy 72 hours after the onset of disease. Preceding acyclovir, gamma globulin, and exchange blood transfusion therapies failed to control the disease. Methylprednisolone pulse therapy led to a drastic improvement of liver function and cytokine storms, and prevented the disease progression to HLH. Sustained levels of plasma and cerebrospinal fluid HSV DNA declined after prolonged acyclovir therapy. Bilateral lesions of the periventricular white matter areas, assessed by magnetic resonance imaging, disappeared at 3 months of age. The infant showed normal growth and development at 4 years of age. Conclusion Early anti-hypercytokinemia therapy using corticosteroid, and prolonged antiviral therapy might only provide the transplantation-free cure of NLF with HSV dissemination. PMID:26495160

  7. Clinical Laboratory Testing in the Era of Directly Acting Antiviral Therapies for Hepatitis C

    PubMed Central

    Wilson, Eleanor M.; Rosenthal, Elana S.; Kattakuzhy, Sarah; Tang, Lydia

    2016-01-01

    SUMMARY Directly acting antiviral (DAA) combination therapies for chronic hepatitis C virus (HCV) infection are highly effective, but treatment decisions remain complex. Laboratory testing is important to evaluate a range of viral, host, and pharmacological factors when considering HCV treatment, and patients must be monitored during and after therapy for safety and to assess the viral response. In this review, we discuss the laboratory tests relevant for the treatment of HCV infection in the era of DAA therapy, grouped according to viral and host factors. PMID:27795306

  8. Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies.

    PubMed

    Zhang, Zhiqing; Li, Shaowei; Gu, Ying; Xia, Ningshao

    2016-11-18

    Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immune deficiency syndrome (AIDS), a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART) but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1. In this review, we describe the key epitopes on the HIV-1 Env protein and the reciprocal broadly neutralizing antibodies, and discuss the ongoing clinical trials of broadly neutralizing and inhibitory antibody therapy as well as antibody combinations, bispecific antibodies, and methods that improve therapeutic efficacy by combining broadly neutralizing antibodies (bNAbs) with latency reversing agents. Compared with ART, HIV-1 therapeutics that incorporate these broadly neutralizing and inhibitory antibodies offer the advantage of decreasing virus load and clearing infected cells, which is a promising prospect in HIV-1 prevention and treatment.

  9. Management of hepatitis C infection in the era of direct-acting antiviral therapy

    NASA Astrophysics Data System (ADS)

    Zain, L. H.; Sungkar, T.

    2018-03-01

    Hepatitis C viral infection globally affects millions of people and commonly results in debilitating complications and mortality. Initial mainstay therapy consisted of pegylated interferon α (pegIFNα) with additional ribavirin that showed unsatisfactory cure rate, common side effects and complicated dosing, contributing to high discontinuation rate. Over the last few years, newer antivirals have been extensively studied, that are Direct-Acting Antivirals (DAAs). Specifically targeting viral protein mainly during replication phase, DAAs showed greater cure rate (commonly measured as sustained virologic response), improved safety profile and shorter treatment duration compared to traditional interferon-ribavirin therapy. Current guidelines have also included Interferon-free, often ribavirin-free, DAAs combinations that suggest promising outcomes. The current review highlights development of rapidly growing hepatitis C treatment including DAAs recommendations.

  10. [Comparative analysis of the effectiveness of antiviral therapy of children with infectious mononucleosis].

    PubMed

    Baranova, I P; Kurmaeva, D Iu

    2013-01-01

    A group of 126 children (4 to 7 years old) with infectious mononucleosis received basic therapy in combination with nonspecific antiviral drugs. The same therapeutic efficiency was observed for cycloferon and genferon light included in complex treatment of infectious mononucleosis in children. The use of cycloferon (10 mg/kg i.m., single daily injection for 10 days) prevents the development of frequent acute respiratory viral infections in the period of convalescence.

  11. Transgenic Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-Mediated Viral Gene Targeting for Antiviral Therapy of Bombyx mori Nucleopolyhedrovirus

    PubMed Central

    Chen, Shuqing; Hou, Chengxiang; Bi, Honglun; Wang, Yueqiang; Xu, Jun; Li, Muwang; James, Anthony A.

    2017-01-01

    ABSTRACT 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. PMID:28122981

  12. Transgenic Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-Mediated Viral Gene Targeting for Antiviral Therapy of Bombyx mori Nucleopolyhedrovirus.

    PubMed

    Chen, Shuqing; Hou, Chengxiang; Bi, Honglun; Wang, Yueqiang; Xu, Jun; Li, Muwang; James, Anthony A; Huang, Yongping; Tan, Anjiang

    2017-04-15

    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.

  13. Changes in Liver Volume in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy

    PubMed Central

    Fitzpatrick, Julie A.; Kim, Jin Un; Cobbold, Jeremy F.L.; McPhail, Mark J.W.; Crossey, Mary M.E.; Bak-Bol, Aluel A.; Zaky, Ashraf; Taylor-Robinson, Simon D.

    2016-01-01

    Aim Liver volumetric analysis has not been used to detect hepatic remodelling during antiviral therapy before. We measured liver volume (LV) changes on volumetric magnetic resonance imaging during hepatitis C antiviral therapy. Methods 22 biopsy-staged patients (median [range] age 4519–65 years; 9F, 13M) with chronic hepatitis C virus infection were studied. LV was measured at the beginning, end of treatment and 6 months post-treatment using 3D T1-weighted acquisition, normalised to patient weight. Liver outlines were drawn manually on 4 mm thick image slices and LV calculated. Inter-observer agreement was analysed. Patients were also assessed longitudinally using biochemical parameters and liver stiffness using Fibroscan™. Results Sustained viral response (SVR) was achieved in 13 patients with a mean baseline LV/kg of 0.022 (SD 0.004) L/kg. At the end of treatment, the mean LV/kg was 0.025 (SD 0.004, P = 0.024 cf baseline LV/kg) and 0.026 (SD 0.004, P = 0.008 cf baseline LV/kg) 6 months post-treatment (P = 0.030 cf baseline, P = 0.004). Body weight-corrected end of treatment LV change was significantly higher in patients with SVR compared to patients not attaining SVR (P = 0.050). End of treatment LV change was correlated to initial ALT (R2 = 0.479, P = 0.037), but not APRI, AST, viral load or liver stiffness measurements. There was a correlation of 0.89 between observers for measured slice thickness. Conclusions LV increased during anti-viral treatment, while the body weight-corrected LV increase persisted post-antiviral therapy and was larger in patients with SVR. PMID:27194891

  14. Changes in Liver Volume in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy.

    PubMed

    Fitzpatrick, Julie A; Kim, Jin Un; Cobbold, Jeremy F L; McPhail, Mark J W; Crossey, Mary M E; Bak-Bol, Aluel A; Zaky, Ashraf; Taylor-Robinson, Simon D

    2016-03-01

    Liver volumetric analysis has not been used to detect hepatic remodelling during antiviral therapy before. We measured liver volume (LV) changes on volumetric magnetic resonance imaging during hepatitis C antiviral therapy. 22 biopsy-staged patients (median [range] age 45(19-65) years; 9F, 13M) with chronic hepatitis C virus infection were studied. LV was measured at the beginning, end of treatment and 6 months post-treatment using 3D T1-weighted acquisition, normalised to patient weight. Liver outlines were drawn manually on 4 mm thick image slices and LV calculated. Inter-observer agreement was analysed. Patients were also assessed longitudinally using biochemical parameters and liver stiffness using Fibroscan™. Sustained viral response (SVR) was achieved in 13 patients with a mean baseline LV/kg of 0.022 (SD 0.004) L/kg. At the end of treatment, the mean LV/kg was 0.025 (SD 0.004, P = 0.024 cf baseline LV/kg) and 0.026 (SD 0.004, P = 0.008 cf baseline LV/kg) 6 months post-treatment (P = 0.030 cf baseline, P = 0.004). Body weight-corrected end of treatment LV change was significantly higher in patients with SVR compared to patients not attaining SVR (P = 0.050). End of treatment LV change was correlated to initial ALT (R (2) = 0.479, P = 0.037), but not APRI, AST, viral load or liver stiffness measurements. There was a correlation of 0.89 between observers for measured slice thickness. LV increased during anti-viral treatment, while the body weight-corrected LV increase persisted post-antiviral therapy and was larger in patients with SVR.

  15. Antiviral therapy for HCV-associated cryoglobulinemic glomerulonephritis: case report and review of the literature.

    PubMed

    Fabrizi, Fabrizio; Fogazzi, Giovanni Battista; Cresseri, Donata; Passerini, Patrizia; Martin, Paul; Donato, Maria Francesca; Rumi, Maria Grazia; Messa, Piergiorgio

    2012-01-01

    We describe the case of a 51-year-old woman with HCV-associated cryoglobulinemic glomerulonephritis (GN). She presented mild deterioration of kidney function, non-nephrotic proteinuria, and active urinary sediment. Kidney biopsy showed features of membranoproliferative changes with some sclerosis. Sustained viral response (SVR) was obtained by 6 months of antiviral therapy (peg-IFN-α2a plus ribavirin). SVR was linked with improvement of kidney function and remission of proteinuria. Clinical and virological remission persists over a 25-month follow-up. This case report emphasizes efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis--preliminary but encouraging results exist. We identified by systematic review of the literature 9 studies (156 unique patients); the pooled estimate of frequency of sustained virological response after IFN-based therapy was 0.49 (95% confidence interval, CI: 0.21, 0.77; p < 0.0005; random effects model). Heterogeneity was found (I(2) = 98.9%, p < 0.0001). Two possible regimens should be considered for the treatment of HCV-associated cryoglobulinemic GN according to the clinical presentation. Immunosuppressive therapy is recommended for HCV-related kidney disease having aggressive course, and recent evidence supports rituximab (RTX) use with a reduced exposure to corticosteroids. We identified six studies (66 unique patients) on RTX therapy for HCV-associated kidney disease; at the end of RTX therapy, the pooled estimate of the mean decrease in proteinuria was 1.4 g/24 h (95% CI: 0.75, 2.05, p < 0.001); The p test for heterogeneity gave a value of 0.94 (I(2) = 0). Several questions related to RTX use remain. HCV-induced GN is uncommon among CKD patients of developed countries, and this clearly hampers prospective controlled clinical trials aimed to evaluate efficacy and safety of antiviral or immunosuppressive therapy in this population. Copyright © 2013 S. Karger AG, Basel.

  16. Elbasvir/Grazoprevir, an Alternative in Antiviral Hepatitis C Therapy in Patients under Amiodarone Treatment

    PubMed Central

    Weiss, Lina; Wustmann, Kerstin; Semmo, Mariam; Schwerzmann, Markus; Semmo, Nasser

    2018-01-01

    A sofosbuvir/ledipasvir combination is part of a first-line treatment of hepatitis C. However, in patients concurrently treated with amiodarone, cardiac side effects have been described, resulting in an official warning in 2015 by the American Food and Drug Administration and the European Medicines Agency when combining those substances. This deprived numerous hepatitis C patients with concurrent cardiovascular problems of receiving this highly effective treatment. Here we present a treatment alternative with an elbasvir/grazoprevir regimen, based on our successful treatment of a patient under concurrent amiodarone therapy. Our observations indicate that patients treated with amiodarone can finally benefit from effective antiviral therapy. PMID:29606942

  17. Cytomegalovirus and ulcerative colitis: Place of antiviral therapy

    PubMed Central

    Pillet, Sylvie; Pozzetto, Bruno; Roblin, Xavier

    2016-01-01

    The link between cytomegalovirus (CMV) infection and inflammatory bowel diseases remains an important subject of debate. CMV infection is frequent in ulcerative colitis (UC) and has been shown to be potentially harmful. CMV reactivation needs to be diagnosed using methods that include in situ detection of viral markers by immunohistochemistry or by nucleic acid amplification techniques. Determination of the density of infection using quantitative tools (numbers of infected cells or copies of the genome) is particularly important. Although CMV reactivation can be considered as an innocent bystander in active flare-ups of refractory UC, an increasing number of studies suggest a deleterious role of CMV in this situation. The presence of colonic CMV infection is possibly linked to a decreased response to steroids and other immunosuppressive agents. Some treatments, notably steroids and cyclosporine A, have been shown to favor CMV reactivation, which seems not to be the case for therapies using anti-tumor necrosis factor drugs. According to these findings, in flare-ups of refractory UC, it is now recommended to look for the presence of CMV reactivation by using quantitative tools in colonic biopsies and to treat them with ganciclovir in cases of high viral load or severe disease. PMID:26877608

  18. Antiviral therapy for hepatitis C: Has anything changed for pregnant/lactating women?

    PubMed

    Spera, Anna Maria; Eldin, Tarek Kamal; Tosone, Grazia; Orlando, Raffaele

    2016-04-28

    Hepatitis C virus (HCV) affects about 3% of the world's population, with the highest prevalence in individuals under 40. The prevalence in pregnant women varies with geographical distribution (highest in developing countries). Prevalence also increases in sub-populations of women at high risk for blood-transmitted infections. HCV infection in pregnancy represents a non-negligible problem. However, most of the past antiviral regimens cannot be routinely offered to pregnant or breastfeeding women because of their side effects. We briefly reviewed the issue of treatment of HCV infection in pregnant/breastfeeding women focusing on the effects of the new direct-acting antivirals on fertility, pregnancy and lactation in animal studies and on the potential risk for humans based on the pharmacokinetic properties of each drug. Currently, all new therapy regimens are contraindicated in this setting because of lack of sufficient safety information and adequate measures of contraception are still routinely recommended for female patients of childbearing potential.

  19. Clearance of hepatitis C viral RNA in cirrhotic patients with antiviral therapy.

    PubMed

    Ono, S K; da Silva, L C; Carrilho, F J; da Fonseca, L E; Mendes, L C; Madruga, C L; Farias, A de Q; Laudanna, A A

    1996-01-01

    Interferon is indicated in chronic infection by hepatitis C virus (HCV), however, cirrhosis has been reported as a bad response factor to the therapy. Fifteen cirrhotic patients with HCV, undergoing treatment with recombinant interferon-alpha, ribavirin and/or ursodeoxycholic acid were studied. They were followed-up and evaluated with dosages of alanine aminotransferase and HCV RNA investigation by PCR technique. Of the 15 cirrhotic patients, seven were negative for HCV RNA after antiviral treatment, however ALT was normal in only three of them. Of the eight patients who were not negative, two had normal ALT. Biochemical-virological discrepancy in the follow-up of the patients after antiviral treatment observed in this study has also been reported by other authors. These reports show that the criteria for response to the treatment is to be established.

  20. Longitudinal Liver Stiffness Assessment in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy

    PubMed Central

    Martinez, Stella M.; Foucher, Juliette; Combis, Jean-Marc; Métivier, Sophie; Brunetto, Maurizia; Capron, Dominique; Bourlière, Marc; Bronowicki, Jean-Pierre; Dao, Thong; Maynard-Muet, Marianne; Lucidarme, Damien; Merrouche, Wassil; Forns, Xavier; de Lédinghen, Victor

    2012-01-01

    Background/Aims Liver stiffness (LS) measurement by means of transient elastography (TE) is accurate to predict fibrosis stage. The effect of antiviral treatment and virologic response on LS was assessed and compared with untreated patients with chronic hepatitis C (CHC). Methods TE was performed at baseline, and at weeks 24, 48, and 72 in 515 patients with CHC. Results 323 treated (62.7%) and 192 untreated patients (37.3%) were assessed. LS experienced a significant decline in treated patients and remained stable in untreated patients at the end of study (P<0.0001). The decline was significant for patients with baseline LS ≥ 7.1 kPa (P<0.0001 and P 0.03, for LS ≥9.5 and ≥7.1 kPa vs lower values, respectively). Sustained virological responders and relapsers had a significant LS improvement whereas a trend was observed in nonresponders (mean percent change −16%, −10% and −2%, for SVR, RR and NR, respectively, P 0.03 for SVR vs NR). In multivariate analysis, high baseline LS (P<0.0001) and ALT levels, antiviral therapy and non-1 genotype were independent predictors of LS improvement. Conclusions LS decreases during and after antiviral treatment in patients with CHC. The decrease is significant in sustained responders and relapsers (particularly in those with high baseline LS) and suggests an improvement in liver damage. PMID:23082200

  1. Antiviral therapy of hepatitis C in 2014: do we need resistance testing?

    PubMed

    Schneider, Maximilian David; Sarrazin, Christoph

    2014-05-01

    The treatment of chronic hepatitis C has fundamentally changed since the approval of the first direct-acting antivirals (DAA) in 2011. In addition to telaprevir and boceprevir, in 2014 two new NS3 protease inhibitors (simeprevir and faldaprevir), one non-nucleoside polymerase inhibitor (sofosbuvir) and one NS5a replication complex inhibitor (daclatasvir) have expanded the treatment options for chronic hepatitis C. Resistance-associated variants (RAV) are naturally produced during the HCV life cycle. The frequency of RAVs within HCV quasispecies mainly depends on their replicational fitness. Variants conferring resistance to nucleos(t)ide analogues have not been detected, and the majority of NS3 protease-resistant variants are present at low frequencies (0.1-3%) before initiation of DAA-based therapies. However, the Q80K variant conferring resistance to simeprevir has been observed in 9-48% of untreated HCV genotype 1a-infected patients, leading to reduced SVR rates. Resistant variants are detectable in the majority of patients with treatment failure to NS3 protease inhibitor- or NS5a inhibitor-based antiviral therapy. Long-term follow-up studies by population-based sequence analysis have shown the disappearance of resistant variants in the majority of patients, with median times to loss of mutations of 4-64weeks. For the nucleotide analogue sofosbuvir, the emergence of the S282T resistant variant has been observed only in single patients, with reversion to wild-type within several weeks. Data are sparse on retreatment of patients with the same DAA or the same class of DAAs. However, retreatment with a different class of DAAs after failure of NS3 protease inhibitor-based therapy has been successful in small studies. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication." Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Resolution of acute hepatitis B-associated aplastic anaemia with antiviral therapy.

    PubMed

    Hendren, Nicholas; Moore, Joseph; Hofmann, Sandra; Rambally, Siayareh

    2017-10-03

    A previously healthy 44-year-old woman presented with 3 days of worsening petechial rash, epistaxis and fatigue. Admission labs revealed pancytopenia, low reticulocyte index and elevated liver enzymes. Bone marrow biopsy demonstrated a profoundly hypocellular bone marrow without dysplasia and additional testing demonstrated an acute hepatitis B infection. In the context of an acute hepatitis B infection, elevated liver enzymes and aplastic anaemia, our patient was diagnosed with severe hepatitis-associated aplastic anaemia due to an acute hepatitis B infection. She was initiated on antiviral therapy with tenofovir and briefly received immunosuppressive therapy with a robust sustained improvement in her blood counts. Acute hepatitis B-associated aplastic anaemia is an exceptionally rare presentation of aplastic anaemia. We present acute hepatitis B-associated aplastic anaemia that resolved with antiviral therapy, which to our knowledge is the second such case reported in the literature and the first using tenofovir. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  3. Cellular immune responses in patients with hepatitis B surface antigen seroclearance induced by antiviral therapy

    PubMed Central

    2011-01-01

    Background The mechanisms by which chronic hepatitis B is completely resolved through antiviral therapy are unknown, and the contribution of acquired T cell immunity to hepatitis B surface antigen (HBsAg) seroclearance has not been investigated. Therefore, we measured the T-cell responses to core and envelope antigens in patients with HBsAg seroclearance. Methods Fourteen subjects with HBsAg seroclearance following antiviral treatment for chronic hepatitis B, 7 HBeAg-positive immunotolerant HBV carriers and 9 HBeAg-negative inactive HBsAg carriers were recruited. HBV-specific T-cell responses to recombinant HBV core (rHBcAg) and envelope (rHBsAg) proteins and pools of core and envelope peptides were measured using an ELISPOT assay detecting interferon-gamma and intracellular cytokine staining (ICS) assays detecting interferon-gamma or interleukin 2. Results Interferon-gamma ELISPOT assays showed a low frequency of weak responses to the rHBsAg and S peptide pool in the HBsAg seroclearance group, and the response frequency to the rHBcAg and the C peptide pool was higher than to the rHBsAg (P < 0.001) and S peptide pool (P = 0.001) respectively. A higher response frequency to C than S peptide pools was confirmed in the interferon-gamma ICS assays for both CD4+ (P = 0.033) and CD8+ (P = 0.040) T cells in the HBsAg seroclearance group. The responses to C and S antigens in the inactive carriers were similar. Conclusions There was a low frequency of CD4+ and CD8+ T cell immune responses to envelope antigens in Chinese subjects with HBsAg seroclearance following antiviral therapy. It is unlikely that these immune responses are responsible for HBsAg seroclearance in these subjects. PMID:21320337

  4. Clinical features and effect of antiviral therapy on anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis C.

    PubMed

    Ferri, Silvia; Muratori, Luigi; Quarneti, Chiara; Muratori, Paolo; Menichella, Rita; Pappas, Georgios; Granito, Alessandro; Ballardini, Giorgio; Bianchi, Francesco B; Lenzi, Marco

    2009-06-01

    Anti-liver/kidney microsomal antibody type 1 (anti-LKM1), a serological marker of type 2 autoimmune hepatitis, is also detected in a small proportion of patients with hepatitis C. This study aimed to evaluate clinical features and effect of antiviral therapy in patients with hepatitis C who are anti-LKM1 positive. Sixty consecutive anti-LKM1 positive and 120 age and sex-matched anti-LKM1 negative chronic hepatitis C patients were assessed at diagnosis and during follow-up. Of these, 26 anti-LKM1 positive and 72 anti-LKM1 negative received antiviral therapy. Anti-LKM1 was detected by indirect immunofluorescence and immunoblot. Number of HCV-infected hepatocytes and intrahepatic CD8+ lymphocytes was determined by immunohistochemistry. At diagnosis anti-LKM1 positive patients had higher IgG levels and more intrahepatic CD8+ lymphocytes (p 0.022 and 0.046, respectively). Viral genotypes distribution and response to therapy were identical. Hepatic flares during antiviral treatment only occurred in a minority of patients in concomitance with anti-LKM1 positivity. Immune system activation is more pronounced in anti-LKM1 positive patients with hepatitis C, possibly representing the expression of autoimmune mechanisms of liver damage. Antiviral treatment is as beneficial in these patients as in anti-LKM1 negative patients, and the rare necroinflammatory flares are effectively controlled by corticosteroids, allowing subsequent resumption of antiviral therapy.

  5. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy.

    PubMed

    Flemming, Jennifer A; Kim, W Ray; Brosgart, Carol L; Terrault, Norah A

    2017-03-01

    Direct-acting antiviral (DAA) therapy, recently approved for patients with decompensated cirrhosis (DC) secondary to hepatitis C virus (HCV), is associated with improved hepatic function. We analyzed trends in liver transplant (LT) wait-listing (WL) to explore potential impact of effective medical therapy on WL registration. This is a cohort study using the Scientific Registry of Transplant Recipients database from 2003 to 2015. A total of 47,591 adults wait-listed for LT from HCV, hepatitis B virus (HBV), and nonalcoholic steatohepatitis (NASH) were identified. LT indication was defined as DC if the Model for End-Stage Liver Disease (MELD) at WL was ≥15 or hepatocellular carcinoma (HCC). Era of listing was divided into interferon (IFN; 2003-2010), protease inhibitor (PI; 2011-2013), and direct-acting antiviral (DAA; 2014-2015). Annual standardized incidence rates of WL were analyzed using Poisson regression. Adjusted incidences of LT WL for DC in HCV patients decreased by 5% in the PI era (P = 0.004) and 32% in the DAA era (P < 0.001) compared to the IFN era. Listing for DC in HBV also decreased in the PI (-17%; P = 0.002) and DAA eras (-24%; P < 0.001). Conversely, WL for DC in NASH increased by 41% in the PI era (P < 0.001) and 81% in the DAA era (P < 0.001). WL for HCC in both the HCV and NASH populations increased in both the PI and DAA eras (P < 0.001 for all) whereas HCC WL in HBV remained stable (P > 0.05 for all). The rate of LT WL for HCV complicated by DC has decreased by over 30% in the era of DAA therapy. Further reductions in WL are anticipated with increased testing, linkage to care, and access to DAA therapy. (Hepatology 2017;65:804-812). © 2016 by the American Association for the Study of Liver Diseases.

  6. Reduced-dose telaprevir-based triple antiviral therapy for recurrent hepatitis C after living donor liver transplantation.

    PubMed

    Ikegami, Toru; Yoshizumi, Tomoharu; Kato, Masaki; Yamamoto, Satomi; Fukuhara, Takasuke; Matsuura, Yoshiharu; Nakamura, Shota; Itoh, Shinji; Shirabe, Ken; Maehara, Yoshihiko

    2014-11-15

    The feasibility of telaprevir-based triple therapy for recurrent hepatitis C after liver transplantation (LT) has not been evaluated in Asian patients. Eleven Japanese patients received reduced-dose telaprevir (1500 mg) and adjusted-dose cyclosporine after LT. Six patients were nonresponders and three were transient responders to dual therapy. Rapid viral response, early viral response, end of treatment response, and sustained viral response were achieved in 27.3%, 90.9%, 90.9%, and 81.8% of patients, respectively. One patient had viral breakthrough at week 8 with a T54A mutation in NS3. Deep sequence analysis showed that the T54A mutation reverted to wild-type after stopping telaprevir administration. Seven patients developed severe anemia, and six received blood transfusions (4-20 U). Their hemoglobin and estimated glomerular filtration rate remained significantly lower than pretreatment values at 36 weeks after treatment. Four patients developed plasma cell hepatitis after completing telaprevir treatment, and it was treated by increasing the immunosuppressants. Although the cyclosporine level/dose ratio was 2.7 times higher at week 4 than before treatment, it was 0.7 times lower at week 36. Reduced-dosed telaprevir-based triple antiviral therapy achieved a high viral clearance rate in Japanese patients after LT. Major adverse events included severe anemia, renal dysfunction, and plasma cell hepatitis.

  7. Antiviral therapy for hepatitis C: Has anything changed for pregnant/lactating women?

    PubMed Central

    Spera, Anna Maria; Eldin, Tarek Kamal; Tosone, Grazia; Orlando, Raffaele

    2016-01-01

    Hepatitis C virus (HCV) affects about 3% of the world’s population, with the highest prevalence in individuals under 40. The prevalence in pregnant women varies with geographical distribution (highest in developing countries). Prevalence also increases in sub-populations of women at high risk for blood-transmitted infections. HCV infection in pregnancy represents a non-negligible problem. However, most of the past antiviral regimens cannot be routinely offered to pregnant or breastfeeding women because of their side effects. We briefly reviewed the issue of treatment of HCV infection in pregnant/breastfeeding women focusing on the effects of the new direct-acting antivirals on fertility, pregnancy and lactation in animal studies and on the potential risk for humans based on the pharmacokinetic properties of each drug. Currently, all new therapy regimens are contraindicated in this setting because of lack of sufficient safety information and adequate measures of contraception are still routinely recommended for female patients of childbearing potential. PMID:27134703

  8. Glycosylation of dengue virus glycoproteins and their interactions with carbohydrate receptors: possible targets for antiviral therapy.

    PubMed

    Idris, Fakhriedzwan; Muharram, Siti Hanna; Diah, Suwarni

    2016-07-01

    Dengue virus, an RNA virus belonging to the genus Flavivirus, affects 50 million individuals annually, and approximately 500,000-1,000,000 of these infections lead to dengue hemorrhagic fever or dengue shock syndrome. With no licensed vaccine or specific antiviral treatments available to prevent dengue infection, dengue is considered a major public health problem in subtropical and tropical regions. The virus, like other enveloped viruses, uses the host's cellular enzymes to synthesize its structural (C, E, and prM/M) and nonstructural proteins (NS1-5) and, subsequently, to glycosylate these proteins to produce complete and functional glycoproteins. The structural glycoproteins, specifically the E protein, are known to interact with the host's carbohydrate receptors through the viral proteins' N-glycosylation sites and thus mediate the viral invasion of cells. This review focuses on the involvement of dengue glycoproteins in the course of infection and the virus' exploitation of the host's glycans, especially the interactions between host receptors and carbohydrate moieties. We also discuss the recent developments in antiviral therapies that target these processes and interactions, focusing specifically on the use of carbohydrate-binding agents derived from plants, commonly known as lectins, to inhibit the progression of infection.

  9. The science of direct-acting antiviral and host-targeted agent therapy.

    PubMed

    Pawlotsky, Jean-Michel

    2012-01-01

    Direct-acting antiviral drugs targeting two major steps of the HCV life cycle, polyprotein processing and replication, and cyclophilin inhibitors, that target a host cell protein required to interact with the replication complex, have reached clinical development. In order to achieve a sustained virological response, that is, a cure of the HCV infection, it is necessary to shut down virus production, to maintain viral inhibition throughout treatment and to induce a significant, slower second-phase decline in HCV RNA levels that leads to definitive clearance of infected cells. Recent findings suggest that the interferon era is coming to an end in hepatitis C therapy and HCV infection can be cured by all-oral interferon-free treatment regimens within 12 to 24 weeks. Further results are awaited that will allow the establishment of an ideal first-line all-oral, interferon-free treatment regimen for patients with chronic HCV infection.

  10. Tangible resources for preparing patients for antiviral therapy for chronic hepatitis C.

    PubMed

    Bonner, Jason E; Barritt, A Sidney; Fried, Michael W; Evon, Donna M

    2012-06-01

    Chronic hepatitis C (HCV) infected patients with coexisting mental health and/or substance abuse issues face significant barriers to treatment and are often deferred. This paper sought to highlight critical pre-treatment strategies and provide tangible resources for HCV clinicians to facilitate preparation and successful treatment of these patients. Guided by the clinical experience of our liver center, a large, tertiary academic medical center, and informed by the extant literature, we summarize pre-treatment strategies and specific resources and recommendations for HCV providers. Four key pre-treatment strategies include: 1) screening for mental health/substance abuse issues using brief, reliable and validated instruments; 2) locating and establishing collaborative care with mental health and substance abuse specialists; 3) using a motivational interviewing communication style; and 4) addressing adherence-related issues. HCV clinicians are in a unique position to prepare patients with coexisting mental health and/or substance abuse issues for antiviral therapy.

  11. [Impact of antiviral therapy on the natural history of hepatitis C virus].

    PubMed

    Fernández Rodriguez, Conrado M; Gutierrez Garcia, Maria Luisa

    2014-12-01

    Chronic hepatitis C virus infection affects around 150 million persons, and 350,000 persons worldwide die of this disease each year. Although the data on its natural history are incomplete, after the acute infection, most patients develop chronic forms of hepatitis C with variable stages of fibrosis. In these patients, continual inflammatory activity can cause significant fibrosis, cirrhosis, decompensation of the liver disease, or hepatocarcinoma. In the next few years, it is expected that hepatitis C virus infection and its complications will significantly increase, as will the incidence of hepatocarcinoma in Spain. This review presents the data on the natural history of hepatitis C virus infection and discusses the potential impact of antiviral therapy on the distinct stages of the disease. Copyright © 2014 Elsevier España, S.L.U. and AEEH y AEG. All rights reserved.

  12. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study.

    PubMed

    Carrión, José A; Navasa, Miquel; García-Retortillo, Montserrat; García-Pagan, Juan Carlos; Crespo, Gonzalo; Bruguera, Miquel; Bosch, Jaime; Forns, Xavier

    2007-05-01

    Recurrence of hepatitis C virus (HCV) infection is a relevant problem of liver transplantation programs. We evaluated the effect of antiviral therapy on disease progression in 81 HCV-infected liver transplantation recipients. Patients with mild hepatitis C recurrence (fibrosis stage F0 to F2, n = 54) were randomized to no treatment (group A, n = 27) or peginterferon alfa-2b/ribavirin for 48 weeks (group B, n = 27). Patients with severe recurrence (F3 to F4, cholestatic hepatitis) were treated (group C, n = 27). All patients (n = 81) underwent a liver biopsy at baseline and after follow-up; paired hepatic venous pressure gradient (HVPG) measurements were available in 51 patients. Thirteen (48%) patients of group B and 5 (18.5%) of group C achieved sustained virological response. Liver fibrosis progressed > or =1 stage in 40 (49%) of 81 patients: 19 (70%) of group A versus 7 (26%) of group B (P = .001) and in 14 (54%) of group C. HVPG increased (6.5 to 13 mm Hg, P < .01) in patients in whom fibrosis worsened, whereas it decreased (5 to 3.5 mm Hg, P = .017) or remained unchanged in those with fibrosis improvement or stabilization, respectively. The only variable independently associated with fibrosis improvement/stabilization was treatment (odds ratio [OR] =3.7, 95% confidence interval [CI] 1.3 to 10, P = .009). Among treated patients, alanine aminotransferase (ALT) normalization and viral clearance were independently associated with histological or hemodynamic improvement/stabilization (OR 5.3, 95% CI 1.5 to 18, P < .01; OR 7.4, 95% CI 1.4 to 38, P = .01; respectively). Our data demonstrate that in liver transplantation recipients, antiviral therapy slows disease progression (particularly in sustained virological responders), as shown by its effects on liver histology and on HVPG.

  13. Direct-Acting Antiviral Therapy Outcomes in Canadian Chronic Hepatitis C Telemedicine Patients.

    PubMed

    Cooper, Curtis L; Hatashita, Holly; Corsi, Daniel J; Parmar, Parmvir; Corrin, Raymond; Garber, Gary

    Many of the 300,000 HCV-infected Canadians live in under-served and remote areas without access to HCV healthcare specialists. Telemedicine (TM) and advances in HCV management can facilitate linkage of these marginalized patients to healthcare. A cohort database analysis was performed on patients followed at The Ottawa Hospital and Regional Viral Hepatitis Program between January 2012 and August 2016. We compared patient characteristics, fibrosis work-up and antiviral treatment outcomes in TM (n = 157) and non-TM (n = 1,130) patients (The Ottawa Hospital Viral Hepatitis Outpatient Clinic) residing in Eastern Ontario. TM patients were more often infected with genotype 3 (25.9% vs. 16.4%), were more commonly Indigenous (7.0% vs. 2.2%) had a history of injection drug use (70.1% vs. 54.9%) and incarceration (46.5% vs 35.5%). Groups were comparable in age (48.9 years), gender (63.7% male) and cirrhotic stage (24.0%). 59.2% of TM patients underwent transient elastography during regional outreach blitzes compared to 61.8% of non-TM patients (p = 0.54). Overall, half as many TM patients initiated antiviral therapy as non-TM patients (27.4% vs. 53.8%, p < 0.001). The introduction of DAA regimens is bridging this gap (22.2% of TM patients vs. 34.3% of non-TM patients). SVR rates with interferon-free, DAA regimens were 94.7% and 94.8% in TM and non-TM groups (p = 0.99). Our TM program engages and retains a population that faces many barriers to effective HCV treatment. TM patients initiated HCV therapy and achieved High SVR rates comparable to those obtained using traditional models of care.

  14. Hepatitis C Virus and Antiviral Drug Resistance.

    PubMed

    Kim, Seungtaek; Han, Kwang-Hyub; Ahn, Sang Hoon

    2016-11-15

    Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens.

  15. Orange juice as dietary source of antioxidants for patients with hepatitis C under antiviral therapy.

    PubMed

    Gonçalves, Danielle; Lima, Claudia; Ferreira, Paula; Costa, Paulo; Costa, Angela; Figueiredo, Walter; Cesar, Thais

    2017-01-01

    Background: HCV causes alterations in liver metabolism, resulting in biochemical and nutritional disorders. Supplementation with antioxidants has been suggested to minimize the diseases effects. Objective: This study assessed whether orange juice, a source of citrus flavonoids and vitamin C, may contribute to the treatment of patients with chronic hepatitis C. Design: Anthropometric, hemodynamic, dietary, and biochemical parameters, CRP and liver enzymes were measured in 43 adult patients of both genders who were diagnosed with chronic hepatitis C and were under antiviral therapy. Twenty-three patients were supplemented with orange juice for eight consecutive weeks, while 20 were enrolled as control group. Results: Following regular use of orange juice, no alterations were found in body mass, fat, and waist circumference. The serum levels of total cholesterol, LDL-cholesterol, CRP and parameters of oxidative stress decreased in the orange juice group. Furthermore, the levels of the liver enzyme AST decreased in those who had high levels before the intervention. Conclusion: The orange juice was a convenient food in the diet of patients due to the increase in antioxidant capacity and decreased inflammation and cholesterol in blood serum, in addition to maintaining body mass, which protect against the harmful effects caused by the chronic hepatitis C virus.​​​.

  16. Orange juice as dietary source of antioxidants for patients with hepatitis C under antiviral therapy

    PubMed Central

    Gonçalves, Danielle; Lima, Claudia; Ferreira, Paula; Costa, Paulo; Costa, Angela; Figueiredo, Walter; Cesar, Thais

    2017-01-01

    ABSTRACT Background: HCV causes alterations in liver metabolism, resulting in biochemical and nutritional disorders. Supplementation with antioxidants has been suggested to minimize the diseases effects. Objective: This study assessed whether orange juice, a source of citrus flavonoids and vitamin C, may contribute to the treatment of patients with chronic hepatitis C. Design: Anthropometric, hemodynamic, dietary, and biochemical parameters, CRP and liver enzymes were measured in 43 adult patients of both genders who were diagnosed with chronic hepatitis C and were under antiviral therapy. Twenty-three patients were supplemented with orange juice for eight consecutive weeks, while 20 were enrolled as control group. Results: Following regular use of orange juice, no alterations were found in body mass, fat, and waist circumference. The serum levels of total cholesterol, LDL-cholesterol, CRP and parameters of oxidative stress decreased in the orange juice group. Furthermore, the levels of the liver enzyme AST decreased in those who had high levels before the intervention. Conclusion: The orange juice was a convenient food in the diet of patients due to the increase in antioxidant capacity and decreased inflammation and cholesterol in blood serum, in addition to maintaining body mass, which protect against the harmful effects caused by the chronic hepatitis C virus.​​​ PMID:28469541

  17. Use of HCV+ Donors Does Not Affect HCV Clearance With Directly Acting Antiviral Therapy But Shortens the Wait Time to Kidney Transplantation.

    PubMed

    Sawinski, Deirdre; Patel, Nikunjkumar; Appolo, Brenda; Bloom, Roy

    2017-05-01

    Hepatitis C virus (HCV) infection is prevalent in the renal transplant population but direct acting antiviral agents (DAA) provide an effective cure of HCV infection without risk of allograft rejection. We report our experience treating 43 renal transplant recipients with 4 different DAA regimens. One hundred percent achieved a sustained viral response by 12 weeks after therapy, and DAA regimens were well tolerated. Recipients transplanted with a HCV+ donor responded equally well to DAA therapy those transplanted with a kidney from an HCV- donor, but recipients of HCV+ organs experienced significantly shorter wait times to transplantation, 485 days (interquartile range, 228-783) versus 969 days (interquartile range, 452-2008; P = 0.02). On this basis, we advocate for a strategy of early posttransplant HCV eradication to facilitate use of HCV+ organs whenever possible. Additional studies are needed to identify the optimal DAA regimen for kidney transplant recipients, accounting for efficacy, timing relative to transplant, posttransplant clinical outcomes, and cost.

  18. Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients.

    PubMed

    Le Cleach, Laurence; Trinquart, Ludovic; Do, Giao; Maruani, Annabel; Lebrun-Vignes, Benedicte; Ravaud, Philippe; Chosidow, Olivier

    2014-08-03

    acyclovir; pooled RR 1.04, 95% CI, 0.71 to 1.49 for famciclovir vs acyclovir; and pooled RR 1.26, 95% CI 0.89 to 1.75 for famciclovir vs valacyclovir). Safety data were sought but were reported as total numbers of adverse events. Owing to risk of bias and inconsistency, there is low quality evidence that suppressive antiviral therapy with acyclovir, valacyclovir or famciclovir in pacients experiencing at least four recurrences of genital herpes per year decreases the number of pacients with at least one recurrence as compared with placebo. Network meta-analysis of the few direct comparisons and the indirect comparisons did not show superiority of one drug over another.

  19. Unfavorable outcome of antiviral therapy in cytomegalovirus-positive ulcerative colitis may be due to inappropriate study inclusion in meta-analysis.

    PubMed

    Wu, Xiao-Wei; Yang, Miao-Fang; Li, Nan; Wang, Fang-Yu

    2015-02-07

    Some previous articles reported that antiviral treatment was effective to reduce the colectomy rate in ulcerative colitis (UC) patients with cytomegalovirus (CMV) infection. Kopylov et al recently carried out a systematic review and meta-analysis to evaluate the impact of antiviral therapy on CMV-positive UC. The results showed that patients who received antiviral treatment had a higher risk of 30-d colectomy. We found that in this meta-analysis, some studies were inappropriately included, leading to an unfavorable outcome of anti-CMV therapy in UC patients.

  20. Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals.

    PubMed

    Prenner, Stacey B; VanWagner, Lisa B; Flamm, Steven L; Salem, Riad; Lewandowski, Robert J; Kulik, Laura

    2017-06-01

    The approval of all-oral direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) has led to the expansion of therapy to include patients with cirrhosis who have hepatocellular carcinoma (HCC). Data on the use of DAAs in HCV+ patients with HCC is limited. The aim of this study was to assess the efficacy of all-oral-DAA regimens in HCV+ cirrhotic patients who have or had HCC compared to those without HCC. A retrospective cohort study was conducted on all cirrhotic patients who were treated for HCV with DAAs at our institution between January 2014 and November 2015. A total of 421 HCV+ patients with cirrhosis were identified, of whom 33% had active or a history of HCC. Failure to achieve sustained virologic response (SVR) occurred in 21% of patients with HCC compared to 12% of patients without HCC (p=0.009). Of the 29 patients with HCC who did not achieve SVR, 27 (93%) occurred when an active tumor was present. DAA therapy in the presence of an inactive tumor or after removal of tumor (resection/transplant) resulted in excellent SVR rates, similar to those without HCC (p<0.0001). In multivariable analysis, the primary predictor of DAA treatment failure was the presence of active HCC at the time of HCV treatment initiation (adjusted odds ratio=8.5, 95% confidence interval=3.90-18.49). The presence of active HCC tumor at the initiation of HCV therapy is significantly associated with all-oral DAA treatment failure. HCV treatment after curative therapies for HCC resulted in excellent SVR. The new medications for hepatitis C have excellent cure rates. However, our study shows that in patients with both liver cancer and hepatitis C, they do not achieve these cure rates. Patients with liver cancer are almost 8 times more likely to fail hepatitis C treatment than patients without liver cancer. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  1. Utilisation of hepatocellular carcinoma screening in Australians at risk of hepatitis B virus-related carcinoma and prescribed anti-viral therapy.

    PubMed

    Sheppard-Law, Suzanne; Zablotska-Manos, Iryna; Kermeen, Melissa; Holdaway, Susan; Lee, Alice; George, Jacob; Zekry, Amany; Maher, Lisa

    2018-07-01

    To investigate hepatocellular carcinoma screening utilisation and factors associated with utilisation among patients prescribed hepatitis B virus anti-viral therapy and at risk of hepatocellular carcinoma. The incidence of hepatocellular carcinoma has increased in Australia over the past three decades with chronic hepatitis B virus infection a major contributor. hepatocellular carcinoma surveillance programs aim to detect cancers early enabling curative treatment options, longer survival and longer times to recurrence. Multi-site cross-sectional survey. An online study questionnaire was administered to eligible participants attending three Sydney tertiary hospitals. Data were grouped into six mutually exclusive hepatocellular carcinoma risk factor categories as per American Association for the Study of Liver Diseases guidelines. All analyses were undertaken in STATA. Logistic regression was used to assess the associations between covariates and screening utilisation. Multivariate models described were assessed using the Hosmer-Lemeshow goodness of fit. Of the 177 participants, 137 (77.4%) self-reported that US had been performed in the last six months. Awareness that screening should be performed and knowing the correct frequency of US screening were independently associated with screening utilisation. Participants who knew that screening should be undertaken were three times more likely to have had pretreatment education or were prescribed hepatitis B virus anti-viral treatment for >4 years. Participants reporting a family history of hepatocellular carcinoma were less likely to know that screening should be undertaken every 6 months. While utilisation of hepatocellular carcinoma surveillance programs was higher in this study than in previous reports, strategies to further improve surveillance remain necessary. Findings from this research form the basis for proposing strategies to improve utilisation of hepatocellular carcinoma screening, inform hepatitis B virus

  2. Significance of day-1 viral response of hepatitis C virus in patients with chronic hepatitis C receiving direct-acting antiviral therapy.

    PubMed

    Toyoda, Hidenori; Kumada, Takashi; Tada, Toshifumi; Yama, Tsuyoki; Mizuno, Kazuyuki

    2018-06-01

    On-treatment response of serum hepatitis C virus (HCV) is reportedly less useful to predict the outcome of anti-HCV therapy with interferon (IFN)-free regimen with direct-acting antivirals than with IFN-based regimens in clinical trials. We evaluated the significance of very early viral response after the start of therapy, which indicates direct HCV response to the drugs, on therapeutic outcome. Reductions in serum HCV-RNA levels were measured at 1 day after the start of therapy in 544 patients who underwent IFN-free direct-acting antiviral regimens. The association between these reductions and the achievement or failure of sustained virologic response (SVR) was evaluated. Patient characteristics did not influence 1-day reduction in serum HCV-RNA except for liver fibrosis. There was no difference in 1-day HCV reduction between SVR and non-SVR patients treated with a 24-week regimen. In contrast, in patients treated with a 12-week regimen, 1-day reduction was significantly greater in SVR than in non-SVR patients (P = 0.0013) and was predictive of SVR versus non-SVR (area under the receiver-operating characteristics curve: 0.80). Whereas the reduction in serum HCV-RNA levels at 1 day after the start of therapy was not associated with treatment outcomes in patients who underwent a 24-week regimen of IFN-free therapy, there was an association in patients receiving a 12-week regimen, and this reduction was predictive of SVR, thus potentially serving as a factor to identify patients at risk of treatment failure. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  3. Modeling Viral Infectious Diseases and Development of Antiviral Therapies Using Human Induced Pluripotent Stem Cell-Derived Systems.

    PubMed

    Trevisan, Marta; Sinigaglia, Alessandro; Desole, Giovanna; Berto, Alessandro; Pacenti, Monia; Palù, Giorgio; Barzon, Luisa

    2015-07-13

    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.

  4. Antiviral therapy after non-surgical tumor ablation in patients with hepatocellular carcinoma associated with hepatitis C virus.

    PubMed

    Hung, Chao-Hung; Lee, Chuan-Mo; Wang, Jing-Houng; Tung, Hung-Da; Chen, Chien-Hung; Lu, Sheng-Nan

    2005-10-01

    Antiviral therapy for chronic hepatitis C virus (HCV) infection has led to a reduction in the incidence of hepatocellular carcinoma (HCC). The purpose of the present paper was to assess whether antiviral therapy might suppress tumor recurrence and influence overall survival in patients with HCV-related HCC who had complete ablation of nodules by non-surgical treatments. Twenty patients with three or fewer nodules of HCV-related HCC who were treated with percutaneous tumor ablation and/or transcatheter arterial embolization received combined interferon (IFN; 3 or 5 million units of IFN alpha-2b thrice weekly) plus ribavirin (1000-1200 mg per day) therapy for 24-48 weeks after complete ablation of lesions. During the same period, an additional 40 age- and sex-matched control patients with similar characteristics of tumors (sizes, numbers and treatment modalities) and severity of liver disease were recruited from the HCC database. Both recurrence-free survival and actuarial survival were evaluated. Of the 20 patients, 16 completed therapy and 10 showed a sustained response with normalization of alanine aminotransferase and negative HCV-RNA at 6 months after therapy completion. Due to severe side-effects experienced by Child B patients, who mostly discontinued antiviral therapy, clinical outcome was analyzed in the Child A treated (n = 16) and control (n = 33) patients. There was no significant difference in the incidence of local recurrence in sustained responders compared with non-responders or control patients (P = 0.174, 0.1284, respectively); but the second recurrence-free interval in the sustained responders was significantly longer than that of non-responders and the control group (P = 0.0141, 0.0243, respectively). Survival in sustained responders was better than in non-responders and control patients (P = 0.0691, 0.0554, respectively). These results indicate that successful antiviral therapy after non-surgical tumor ablation for HCV-related HCC may lower tumor

  5. Effects of transarterial chemoembolization combined with antiviral therapy on HBV reactivation and liver function in HBV-related hepatocellular carcinoma patients with HBV-DNA negative.

    PubMed

    Wang, Kai; Jiang, Guomin; Jia, Zhongzhi; Zhu, Xiaoli; Ni, Caifang

    2018-06-01

    The aim of this study was to investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in primary hepatocellular carcinoma (HCC) patients with HBV-DNA negative and to evaluate the effects of TACE combined with antiviral therapy. This prospective study involved 98 patients with HBV-related and HBV-DNA negative HCC (HBV DNA < 10 copies/mL) underwent TACE procedures with serial HBV DNA tests. Patients were divided into the antiviral treatment group and the no-antiviral group. The antiviral group received entecavir antiviral therapy, and the other group received no antiviral therapy. Two groups of patients were compared in rate of HBV reactivation and liver function before and after only 1 session of TACE in average 1-month follow-up after operation. P < .05 indicated differences with a statistical significance. HBV reactivation occurred in 11 patients in the nonantiviral group (11/47, 23.4%) but only 3 patients in the antiviral group (3/51, 5.9%, P < .05). On multivariate analysis, HBeAg-positive status, number of tumors more than 3, and absence of antiviral therapy were the independent risk predictor of HBV reactivation. Liver function indicators did not differ significantly between the antiviral group and the nonantiviral group in 5 days after TACE. However, the level of alanine aminotransferase and bilirubin were raised and albumin was reduced at the HBV reactivation group compared with no HBV reactivation group (P < .05). At 1 month after TACE, liver function indicators did not differ significantly between the HBV reactivation group and without HBV reactivation group. HCC patients with HBV DNA negative still remain associated with risk of HBV reactivation after TACE. HBeAg-positive, number of tumors more than 3, and absence of antiviral therapy in HCC patients after TACE have a higher risk of HBV reactivation. Antiviral therapy can reduce the risk of reactivation, helping improve liver function

  6. Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway

    PubMed Central

    Pattabhi, Sowmya; Wilkins, Courtney R.; Dong, Ran; Knoll, Megan L.; Posakony, Jeffrey; Kaiser, Shari; Mire, Chad E.; Wang, Myra L.; Ireton, Renee C.; Geisbert, Thomas W.; Bedard, Kristin M.; Iadonato, Shawn P.

    2015-01-01

    ABSTRACT The cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays a critical role in antiviral immunity to drive the expression of innate immune response genes, including those encoding antiviral factors, type 1 interferon, and immune modulatory cytokines, that act in concert to restrict virus replication. Thus, small molecule agonists that can promote IRF3 activation and induce innate immune gene expression could serve as antivirals to induce tissue-wide innate immunity for effective control of virus infection. We identified small molecule compounds that activate IRF3 to differentially induce discrete subsets of antiviral genes. We tested a lead compound and derivatives for the ability to suppress infections caused by a broad range of RNA viruses. Compound administration significantly decreased the viral RNA load in cultured cells that were infected with viruses of the family Flaviviridae, including West Nile virus, dengue virus, and hepatitis C virus, as well as viruses of the families Filoviridae (Ebola virus), Orthomyxoviridae (influenza A virus), Arenaviridae (Lassa virus), and Paramyxoviridae (respiratory syncytial virus, Nipah virus) to suppress infectious virus production. Knockdown studies mapped this response to the RIG-I-like receptor pathway. This work identifies a novel class of host-directed immune modulatory molecules that activate IRF3 to promote host antiviral responses to broadly suppress infections caused by RNA viruses of distinct genera. IMPORTANCE Incidences of emerging and reemerging RNA viruses highlight a desperate need for broad-spectrum antiviral agents that can effectively control infections caused by viruses of distinct genera. We identified small molecule compounds that can

  7. Reduced Mortality of Cytomegalovirus Pneumonia After Hematopoietic Cell Transplantation Due to Antiviral Therapy and Changes in Transplantation Practices

    PubMed Central

    Erard, Veronique; Guthrie, Katherine A.; Seo, Sachiko; Smith, Jeremy; Huang, MeeiLi; Chien, Jason; Flowers, Mary E. D.; Corey, Lawrence; Boeckh, Michael

    2015-01-01

    Background. Despite major advances in the prevention of cytomegalovirus (CMV) disease, the treatment of CMV pneumonia in recipients of hematopoietic cell transplant remains a significant challenge. Methods. We examined recipient, donor, transplant, viral, and treatment factors associated with overall and attributable mortality using Cox regression models. Results. Four hundred twenty-one cases were identified between 1986 and 2011. Overall survival at 6 months was 30% (95% confidence interval [CI], 25%–34%). Outcome improved after the year 2000 (all-cause mortality: adjusted hazard ratio [aHR], 0.7 [95% CI, .5–1.0]; P = .06; attributable mortality: aHR, 0.6 [95% CI, .4–.9]; P = .01). Factors independently associated with an increased risk of all-cause and attributable mortality included female sex, elevated bilirubin, lymphopenia, and mechanical ventilation; grade 3/4 acute graft-vs-host disease was associated with all-cause mortality only. An analysis of patients who received transplants in the current preemptive therapy era (n = 233) showed only lymphopenia and mechanical ventilation as significant risk factors for overall and attributable mortality. Antiviral treatment with ganciclovir or foscarnet was associated with improved outcome compared with no antiviral treatment. However, the addition of intravenous pooled or CMV-specific immunoglobulin to antiviral treatment did not seem to improve overall or attributable mortality. Conclusions. Outcome of CMV pneumonia showed a modest improvement over the past 25 years. However, advances seem to be due to antiviral treatment and changes in transplant practices rather than immunoglobulin-based treatments. Novel treatment strategies for CMV pneumonia are needed. PMID:25778751

  8. Provider-patient in-office discussions of response to hepatitis C antiviral therapy and impact on patient comprehension.

    PubMed

    Hamilton, Heidi E; Nelson, Meaghan; Martin, Paul; Cotler, Scott J

    2006-04-01

    Providers need to communicate projected response rates effectively to enable patients with hepatitis C virus to make informed decisions about therapy. This study used interactional sociolinguistics (1) to evaluate how gastroenterologists and allied health professionals communicate information regarding response rates to antiviral therapy, (2) to determine how these discussions relate to where the patient is in the continuum of evaluation and treatment, (3) to assess whether patients were aligned with providers in their perceptions of response rates after office visits, and (4) to identify factors that improve provider-patient alignment. Gastroenterologists, allied health professionals, and patients with hepatitis C virus were videotaped and audiotaped during regularly scheduled visits. Postvisit interviews were conducted separately with patients and providers. Visits and postvisits were transcribed and analyzed using validated sociolinguistic techniques. The phase of hepatitis C virus treatment shaped the benchmarks of response talk, although across the treatment continuum providers overwhelmingly made strategic use of positive statistics, providing motivation. In postvisit interviews, 55% of providers and patients were aligned on response rates. Patients with a favorable outcome and patients who asked response-related questions in the visit were more likely to be aligned with providers. Areas identified for improvement included the tendency to discuss response rates before an individualized assessment could be made, balancing motivation and accuracy, and assessing the patient's perspective before delivering any bad news, if necessary. Sociolinguistic analysis provides a powerful tool to evaluate provider-patient interactions and to identify ways to improve in-office communication regarding antiviral therapy.

  9. Direct-Acting Antiviral Therapy for Chronic HCV Infection Results in Liver Stiffness Regression Over 12 Months Post-treatment.

    PubMed

    Chan, Justin; Gogela, Neliswa; Zheng, Hui; Lammert, Sara; Ajayi, Tokunbo; Fricker, Zachary; Kim, Arthur Y; Robbins, Gregory K; Chung, Raymond T

    2018-02-01

    Liver fibrosis stage determines risk of morbidity and mortality from chronic hepatitis C virus (HCV) infection. Prior data have shown long-term reversal of liver fibrosis, measured by vibration-controlled transient elastography (VCTE), in patients successfully treated with interferon-based therapies. Our study sought to determine the effect of treatment with modern HCV direct-acting antiviral (DAA) therapy on noninvasive liver fibrosis measurements. A total of 70 patients had VCTE-based liver stiffness measurement (LSM) taken before treatment, directly after treatment completion, and at least 12 months after completion of DAA therapy. Our primary outcome was a >30% improvement in VCTE score at the end of follow-up, relative to baseline. The sustained virologic response rate in our cohort was 95.7%. In our cohort, 34 (48.6%) met the primary outcome. Those who had baseline elevated alanine aminotransferase (OR 3.27; 95% CI 1.13-9.47) and genotype 1 (OR 14.63; 95% CI 1.70-125.83) had higher odds of meeting that outcome, and this remained significant after adjusting for age, baseline body mass index, gender, baseline elevated alkaline phosphatase levels, treatment experience, liver transplant status, smoking, and baseline liver stiffness. Treatment of chronic HCV with modern DAA therapy was associated with a significant improvement in LSM by VCTE measurement, suggesting possible early improvement in liver fibrosis along with resolution of inflammation over the first year after treatment completion.

  10. Why are some HIV/AIDS patients reluctant to receive antiviral therapy as soon as possible in China?

    PubMed

    Sun, Yang; Lu, Hongzhou

    2014-06-01

    In more than 20 years of medical practice, a surprising phenomenon has often occurred: some patients with acquired immunodeficiency syndrome (AIDS) decide not to go to the hospital and they do not let others know that they are suffering from the disease unless they believe that they are dieing. Zhang Shan (a pseudonym) is one such patient with human immunodeficiency virus (HIV)/AIDS who was reluctant to receive antiviral therapy as soon as possible, and this paper shares Zhang's story as he related it. Clearly, there are numerous views as to why patients in China behave as Zhang did. Presented here are several reasons, including society, history, morality and ideology, family, and education. Although all of these reasons do play a role, the patient's mindset and behavior is the most significant reason for a patient's reluctance to seek treatment or disclose his/her status. If the individual patient's mindset and behavior are not dealt with effectively, then HIV/AIDS can continue to spread and threaten additional lives and even the fabric of society. This paper analyzes the reasons why patients are hesitant to receive antiviral therapy, but this paper also suggests steps healthcare personnel can take to encourage patients to seek treatment. Such steps can save the lives of current patients with HIV/AIDS. In addition, sound public health measures and a rational approach to treatment are important to helping potential patients with HIV/AIDS.

  11. Week 4 viral load predicts long-term suppression of hepatitis B virus DNA during antiviral therapy: improving hepatitis B treatment in the real world.

    PubMed

    Truong, J; Shadbolt, B; Ooi, M; Chitturi, S; Kaye, G; Farrell, G C; Teoh, N C

    2017-01-01

    Entecavir and tenofovir potently suppress hepatitis B virus (HBV) replication so that serum HBV DNA levels <20 IU/mL can be achieved after 2 years. Despite this, inadequate suppression is reported in >20% of cases for unclear reasons. We tested whether 4-week viral load (VL) assessment could improve 96-week treatment outcome. Data on all chronic hepatitis B patients treated with entecavir or tenofovir between 2005 and 2014 were entered prospectively. Full data capture included pre-treatment, weeks 4, 24, 48 and 96 HBV DNA titre, HBeAg, age, gender, antiviral agent and dose escalation. Compliance data were compiled from pharmacy records, doctors' letters and clinic bookings/attendance. Time to achieve complete viral suppression (HBV DNA < 20 IU/mL) was graphed using Kaplan-Meier curves. Factors affecting this were examined using a multivariate Cox Proportional Hazard model. Among 156 patients treated, 72 received entecavir and 84 tenofovir. Pre-treatment HBV DNA titre, 4-week assessment and compliance impacted significantly on time to complete viral suppression. At 96 weeks, 90% of those assessed as compliant by 4-week HBV DNA had complete viral suppression versus 50% followed by 6-month VL estimation. Continuing care by the same physician was related to 4-week VL testing and optimal compliance. Medium-term outcomes of HBV antiviral therapy are improved by early on-treatment VL testing, facilitating patient engagement and improved compliance. The observation that 90% complete viral suppression after 2 years monotherapy is achievable in a routine clinic setting questions the need for combination therapy in HBV cases with suboptimal response. © 2016 Royal Australasian College of Physicians.

  12. Cost-effectiveness analysis of antiviral therapy in patients with advanced hepatitis B virus-related hepatocellular carcinoma treated with sorafenib.

    PubMed

    Zhang, Pengfei; Yang, Yu; Wen, Feng; Wheeler, John; Fu, Ping; Li, Qiu

    2016-12-01

    Antiviral therapy has been demonstrated to significantly improve the survival in patients with advanced hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The aim of the study was to investigate the cost-effectiveness of antiviral therapy in patients with advanced HBV-related HCC treated with sorafenib. To conduct the analysis, a Markov model comprising three health states (progression-free survival, progressive disease, and death) was created. The efficacy data were derived from medical records. Cost data were collected based on the Chinese national drug prices. Utility data came from the previously published studies. One-way sensitivity analyses as well as probabilistic sensitivity analyses were performed to explore model uncertainties. In the base-case analysis, addition of antiviral therapy to sorafenib generated an effectiveness of 0.68 quality-adjusted life years (QALYs) at a cost of $25 026.04, while sorafenib monotherapy gained an effectiveness of 0.42 QALYs at a cost of $20 249.64. The incremental cost-effectiveness ratio (ICER) was $18 370.77/QALY for antiviral therapy group versus non-antiviral therapy group. On the other hand, the ICER between the two groups in patients with high or low HBV-DNA load, with or without cirrhosis, normal or elevated alanine aminotransferase/aspartate aminotransferase were $16 613.97/QALY, $19 774.16/QALY, $14 587.66/QALY, $19 873.84/QALY, $17 947.07/QALY, and $18 785.58/QALY, respectively. Based on the cost-effectiveness threshold ($20 301.00/QALY in China), addition of antiviral therapy to sorafenib is considered to be a cost-effective option compared with sorafenib monotherapy in patients with advanced HBV-related HCC in China from the patient's perspective. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  13. Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

    PubMed

    Yoo, S H; Kwon, J H; Nam, S W; Kim, H Y; Kim, C W; You, C R; Choi, S W; Cho, S H; Han, J-Y; Song, D S; Chang, U I; Yang, J M; Lee, H L; Lee, S W; Han, N I; Kim, S-H; Song, M J; Hwang, S; Sung, P S; Jang, J W; Bae, S H; Choi, J Y; Yoon, S K

    2018-04-16

    Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response. © 2018 John Wiley & Sons Ltd.

  14. ISG15 Functions as an Interferon-Mediated Antiviral Effector Early in the Murine Norovirus Life Cycle

    PubMed Central

    Rodriguez, Marisela R.; Monte, Kristen; Thackray, Larissa B.

    2014-01-01

    ABSTRACT Human noroviruses (HuNoV) are the leading cause of nonbacterial gastroenteritis worldwide. Similar to HuNoV, murine noroviruses (MNV) are enteric pathogens spread via the fecal-oral route and have been isolated from numerous mouse facilities worldwide. Type I and type II interferons (IFN) restrict MNV-1 replication; however, the antiviral effectors impacting MNV-1 downstream of IFN signaling are largely unknown. Studies using dendritic cells, macrophages, and mice deficient in free and conjugated forms of interferon-stimulated gene 15 (ISG15) revealed that ISG15 conjugation contributes to protection against MNV-1 both in vitro and in vivo. ISG15 inhibited a step early in the viral life cycle upstream of viral genome transcription. Directly transfecting MNV-1 RNA into IFN-stimulated mouse embryonic fibroblasts (MEFs) and bone marrow-derived dendritic cells (BMDC) lacking ISG15 conjugates bypassed the antiviral activity of ISG15, further suggesting that ISG15 conjugates restrict the MNV-1 life cycle at the viral entry/uncoating step. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of early stages of MNV-1 replication. IMPORTANCE Type I IFNs are important in controlling murine norovirus 1 (MNV-1) infections; however, the proteins induced by IFNs that restrict viral growth are largely unknown. This report reveals that interferon-stimulated gene 15 (ISG15) mitigates MNV-1 replication both in vitro and in vivo. In addition, it shows that ISG15 inhibits MNV-1 replication by targeting an early step in the viral life cycle, MNV-1 entry and/or uncoating. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of viral entry/uncoating. PMID:24899198

  15. Antiviral therapy in cytomegalovirus-positive ulcerative colitis: A systematic review and meta-analysis

    PubMed Central

    Kopylov, Uri; Eliakim-Raz, Noa; Szilagy, Andrew; Seidman, Ernest; Ben-Horin, Shomron; Katz, Lior

    2014-01-01

    AIM: To evaluate the impact of antiviral treatment on cytomegalovirus (CMV)-positive ulcerative colitis patients. METHODS: We performed a systematic review and meta-analysis (MA) of comparative cohort and case-control studies published between January 1966 and March 2013. Studies focusing on colectomy series and studies including only less than 3 patients in the treated or non-treated arm were excluded. The primary outcome was colectomy within 30 d of diagnosis. Secondary outcomes included colectomy during the follow-up period Subgroup analyses by method of detection of CMV, study design, risk of bias and country of origin were performed. Quality of studies was evaluated according to modified New-Castle Ottawa Scale. RESULTS: After full-text review, nine studies with a total of 176 patients were included in our MA. All the included studies were of low to moderate quality. Patients who have received antiviral treatment had a higher risk of 30-d colectomy (OR = 2.40; 95%CI: 1.05-5.50; I2 = 37.2%). A subgroup analysis including only patients in whom CMV diagnosis was based did not demonstrate a significant difference between the groups (OR = 3.41; 95%CI: 0.39-29.83; I2 = 56.9%). Analysis of long-term colectomy rates was possible for 6 studies including 110 patients. No statistically significant difference was found between the treated and untreated groups (OR = 1.71; 95%CI: 0.71-4.13; 6 studies, I2 = 0%). Analysis of mortality rate was not possible due to a very limited number of cases. Stratification of the outcomes by disease severity was not possible. CONCLUSION: No positive association between antiviral treatment and a favorable outcome was demonstrated. These findings should be interpreted cautiously due to primary studies’ quality and potential biases. PMID:24627606

  16. Antiviral therapy in cytomegalovirus-positive ulcerative colitis: a systematic review and meta-analysis.

    PubMed

    Kopylov, Uri; Eliakim-Raz, Noa; Szilagy, Andrew; Seidman, Ernest; Ben-Horin, Shomron; Katz, Lior

    2014-03-14

    To evaluate the impact of antiviral treatment on cytomegalovirus (CMV)-positive ulcerative colitis patients. We performed a systematic review and meta-analysis (MA) of comparative cohort and case-control studies published between January 1966 and March 2013. Studies focusing on colectomy series and studies including only less than 3 patients in the treated or non-treated arm were excluded. The primary outcome was colectomy within 30 d of diagnosis. Secondary outcomes included colectomy during the follow-up period Subgroup analyses by method of detection of CMV, study design, risk of bias and country of origin were performed. Quality of studies was evaluated according to modified New-Castle Ottawa Scale. After full-text review, nine studies with a total of 176 patients were included in our MA. All the included studies were of low to moderate quality. Patients who have received antiviral treatment had a higher risk of 30-d colectomy (OR = 2.40; 95%CI: 1.05-5.50; I² = 37.2%). A subgroup analysis including only patients in whom CMV diagnosis was based did not demonstrate a significant difference between the groups (OR = 3.41; 95%CI: 0.39-29.83; I² = 56.9%). Analysis of long-term colectomy rates was possible for 6 studies including 110 patients. No statistically significant difference was found between the treated and untreated groups (OR = 1.71; 95%CI: 0.71-4.13; 6 studies, I² = 0%). Analysis of mortality rate was not possible due to a very limited number of cases. Stratification of the outcomes by disease severity was not possible. No positive association between antiviral treatment and a favorable outcome was demonstrated. These findings should be interpreted cautiously due to primary studies' quality and potential biases.

  17. Viral infection and antiviral therapy in the neonatal intensive care unit.

    PubMed

    Barford, Galina; Rentz, Alison C; Faix, Roger G

    2004-01-01

    Viral diseases are leading causes of mortality and morbidity among infants requiring care in the neonatal intensive care unit (NICU), with ongoing discoveries of new viral pathology likely to add to the burdens posed. Many viral diseases in NICU infants are undiagnosed or appreciated only late in the course because of subtle or asymptomatic presentation, confusion with bacterial disease, and failure to consider viral disease. We present an overview of viral disease in NICU infants, with emphasis on pharmacologic agents currently employed for prophylaxis and treatment of such diseases. Advances in molecular biology and popular demand to develop antiviral agents for viral diseases (eg, human immunodeficiency virus) offer great promise for the future.

  18. Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy.

    PubMed

    To, Eunice E; Vlahos, Ross; Luong, Raymond; Halls, Michelle L; Reading, Patrick C; King, Paul T; Chan, Christopher; Drummond, Grant R; Sobey, Christopher G; Broughton, Brad R S; Starkey, Malcolm R; van der Sluis, Renee; Lewin, Sharon R; Bozinovski, Steven; O'Neill, Luke A J; Quach, Tim; Porter, Christopher J H; Brooks, Doug A; O'Leary, John J; Selemidis, Stavros

    2017-07-12

    The imminent threat of viral epidemics and pandemics dictates a need for therapeutic approaches that target viral pathology irrespective of the infecting strain. Reactive oxygen species are ancient processes that protect plants, fungi and animals against invading pathogens including bacteria. However, in mammals reactive oxygen species production paradoxically promotes virus pathogenicity by mechanisms not yet defined. Here we identify that the primary enzymatic source of reactive oxygen species, NOX2 oxidase, is activated by single stranded RNA and DNA viruses in endocytic compartments resulting in endosomal hydrogen peroxide generation, which suppresses antiviral and humoral signaling networks via modification of a unique, highly conserved cysteine residue (Cys98) on Toll-like receptor-7. Accordingly, targeted inhibition of endosomal reactive oxygen species production abrogates influenza A virus pathogenicity. We conclude that endosomal reactive oxygen species promote fundamental molecular mechanisms of viral pathogenicity, and the specific targeting of this pathogenic process with endosomal-targeted reactive oxygen species inhibitors has implications for the treatment of viral disease.Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.

  19. Examining Hepatitis, A and B Vaccination, and HBV Reactivation Monitoring During Direct-Acting Antiviral Therapy for Hepatitis C.

    PubMed

    Davison, John; O'Shea, Amy; Waterbury, Nancee; Villalvazo, Yolanda

    2018-05-30

    The objective of this study was to examine Hepatitis A (HAV) and Hepatitis B (HBV) screening, and the risk of HBV reactivation during Hepatitis C (HCV) therapy with direct-acting antivirals (DAAs). A retrospective chart review was performed of patients treated with second generation DAA therapy from January 2014 to September 2016 at the Iowa City VA Healthcare System. In total 409 patients initiated HCV treatment, 308 (75%) and 241 (59%) were HAV and HBV vaccine eligible, respectively. Among those, 24 (8%) received a HAV vaccine, while only 20 (8%) received a HBV vaccine. Of these, 7 patients initiating an immunization in the clinic had record of completing the series. Further, 101 patients had a reactive Hepatitis B core Antibody indicating previous HBV infection, and 3 of these were tested for HBV reactivation during HCV therapy. Overall, the assessment found low rates of HAV and HBV vaccine administration, indicating missed opportunities for preventative care during HCV therapy. With the known risk of HBV reactivation with DAAs, the need for HAV and HBV screening is essential.

  20. Music as therapy in early history.

    PubMed

    Thaut, Michael H

    2015-01-01

    The notion of music as therapy is based on ancient cross-cultural beliefs that music can have a "healing" effect on mind and body. Explanations for the therapeutic mechanisms in music have almost always included cultural and social science-based causalities about the uses and functions of music in society. However, it is also important to note that the view of music as "therapy" was also always strongly influenced by the view and understanding of the concepts and causes of disease. Magical/mystical concepts of illness and "rational" medicine probably lived side by side for thousands of years. Not until the late-nineteenth and early-twentieth centuries were the scientific foundations of medicine established, which allowed the foundations of music in therapy to progress from no science to soft science and most recently to actual brain science. Evidence for "early music therapy" will be discussed in four broad historical-cultural divisions: preliterate cultures; early civilizations in Mesopotamia, Egypt, Israel; Greek Antiquity; Middle Ages, Renaissance, and Baroque. In reviewing "early music therapy" practice, from mostly unknown periods of early history (using preliterate cultures as a window) to increasingly better documented times, including preserved notation samples of actual "healing" music, five theories and applications of early music therapy can be differentiated. © 2015 Elsevier B.V. All rights reserved.

  1. Zika plasma viral dynamics in nonhuman primates provides insights into early infection and antiviral strategies

    PubMed Central

    Best, Katharine; Guedj, Jeremie; Madelain, Vincent; de Lamballerie, Xavier; Lim, So-Yon; Osuna, Christa E.; Whitney, James B.; Perelson, Alan S.

    2017-01-01

    The recent outbreak of Zika virus (ZIKV) has been associated with fetal abnormalities and neurological complications, prompting global concern. Here we present a mathematical analysis of the within-host dynamics of plasma ZIKV burden in a nonhuman primate model, allowing for characterization of the growth and clearance of ZIKV within individual macaques. We estimate that the eclipse phase for ZIKV, the time between cell infection and viral production, is most likely short (∼4 h), the median within-host basic reproductive number R0 is 10.7, the rate of viral production is rapid (>25,000 virions d−1), and the lifetime of an infected cell while producing virus is ∼5 h. We also estimate that the minimum number of virions produced by an infected cell over its lifetime is ∼5,500. We assess the potential effect of an antiviral treatment that blocks viral replication, showing that the median time to undetectable plasma viral load (VL) can be reduced from ∼5 d to ∼3 d with a drug concentration ∼15 times the drug’s EC50 when treatment is given prophylactically starting at the time of infection. In the case of favipiravir, a polymerase inhibitor with activity against ZIKV, we predict a dose of 150 mg/kg given twice a day initiated at the time of infection can reduce the peak median VL by ∼3 logs and shorten the time to undetectable median VL by ∼2 d, whereas treatment given 2 d postinfection is mostly ineffective in accelerating plasma VL loss in macaques. PMID:28765371

  2. Anti-viral therapy is associated with improved survival but is underutilised in patients with hepatitis B virus-related hepatocellular carcinoma: real-world east and west experience.

    PubMed

    Chen, V L; Yeh, M-L; Le, A K; Jun, M; Saeed, W K; Yang, J D; Huang, C-F; Lee, H Y; Tsai, P-C; Lee, M-H; Giama, N; Kim, N G; Nguyen, P P; Dang, H; Ali, H A; Zhang, N; Huang, J-F; Dai, C-Y; Chuang, W-L; Roberts, L R; Jun, D W; Lim, Y-S; Yu, M-L; Nguyen, M H

    2018-07-01

    Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti-viral therapy affects survival after HCC diagnosis. This was an international multicentre cohort study of 2518 HBV-related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti-viral therapy and cirrhosis on patients' risk of death. Approximately, 48% of patients received anti-viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti-viral therapy would have been indicated for >60% of the patients not on anti-viral therapy based on American criteria. Patients with cirrhosis had lower 5-year survival (34% vs 46%; P < 0.001) while patients receiving anti-viral therapy had increased 5-year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti-viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001). Anti-viral therapy improved overall survival in patients with HBV-related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti-viral therapy in HBV-related HCC and better linkage-to-care for HBV patients are needed. © 2018 John Wiley & Sons Ltd.

  3. Effects of Smoking on Pegylated Interferon alpha 2a and First Generation Protease Inhibitor-based Antiviral Therapy in Naïve Patients Infected with Hepatitis C Virus Genotype 1.

    PubMed

    Zimmermann, Tim; Hueppe, Dietrich; Mauss, Stefan; Buggisch, Peter; Pfeiffer-Vornkahl, Heike; Grimm, Daniel; Galle, Peter R; Alshuth, Ulrich

    2016-03-01

    Smoking has multiple effects on factors influencing hepatitis C and antiviral therapy, including lipid metabolism, fibrosis, platelet count and adherence aspects. The aim of this analysis was to determine the impact of smoking on hepatitis C virus antiviral therapy. Data of two cohorts of an observational multicenter study including therapy-naïve patients infected with genotype 1 hepatitis C virus (HCV) treated with dual antiviral therapy (n=7,796) with pegylated interferon alpha 2a in combination with ribavirin, or triple antiviral therapy (n=1,122) containing telaprevir or boceprevir, were analysed. In the univariate matched pair analysis of dual antiviral therapy patients (n=584), smoking was significantly associated with lower sustained viral response rates (p=0.026, OR 0.69 CI: 0.50 - 0.96). The effect of smoking on sustained viral response remained significant (p=0.028, OR 0.67 CI: 0.47 - 0.96) in the multivariate analysis when adjusting for all other baseline parameters with a significant association in the univariate analysis, i.e. diabetes, fibrosis, body mass index, transaminases and baseline viral load. Under protease inhibitors the influence of smoking on virological response did not arise. Smoking has a negative impact on antiviral therapy in naïve patients infected with HCV genotype 1 independently of age, gender, history of drug use or alcoholic liver disease. The effects of smoking might be overcome by the new antiviral agents.

  4. Stop codons in the hepatitis B surface proteins are enriched during antiviral therapy and are associated with host cell apoptosis

    SciTech Connect

    Colledge, Danielle; Soppe, Sally; Yuen, Lilly

    Premature stop codons in the hepatitis B virus (HBV) surface protein can be associated with nucleos(t)ide analogue resistance due to overlap of the HBV surface and polymerase genes. The aim of this study was to determine the effect of the replication of three common surface stop codon variants on the hepatocyte. Cell lines were transfected with infectious HBV clones encoding surface stop codons rtM204I/sW196*, rtA181T/sW172*, rtV191I/sW182*, and a panel of substitutions in the surface proteins. HBsAg was measured by Western blotting. Proliferation and apoptosis were measured using flow cytometry. All three surface stop codon variants were defective in HBsAg secretion.more » Cells transfected with these variants were less proliferative and had higher levels of apoptosis than those transfected with variants that did not encode surface stop codons. The most cytopathic variant was rtM204I/sW196*. Replication of HBV encoding surface stop codons was toxic to the cell and promoted apoptosis, exacerbating disease progression. - Highlights: •Under normal circumstances, HBV replication is not cytopathic. •Premature stop codons in the HBV surface protein can be selected and enriched during nucleos(t)ide analogue therapy. •Replication of these variants can be cytopathic to the cell and promote apoptosis. •Inadequate antiviral therapy may actually promote disease progression.« less

  5. Improvement of liver stiffness in patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response.

    PubMed

    Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori; Mizuno, Kazuyuki; Sone, Yasuhiro; Kataoka, Saki; Hashinokuchi, Shinichi

    2017-12-01

    There is insufficient research on whether direct-acting antiviral (DAA) therapy can improve liver fibrosis in patients with chronic hepatitis C virus (HCV). We evaluated sequential changes in liver stiffness using shear wave elastography in patients with HCV who received DAA therapy. A total of 210 patients with HCV who received daclatasvir and asunaprevir therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness, as evaluated by shear wave elastography, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), and at 24 weeks after EOT (SVR24). Alanine aminotransferase levels (ALT) decreased over time, and there were significant differences between baseline and EOT and between EOT and SVR24. Although platelet counts did not significantly differ between baseline and EOT, they increased significantly from EOT to SVR24. The median (interquartile range) liver stiffness values at baseline, EOT, and SVR24 were 10.2 (7.7-14.7), 8.8 (7.1-12.1), and 7.6 (6.3-10.3) kPa, respectively (P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). Additionally, in patients with ALT ≤ 30 (indicating low necroinflammatory activity in the liver) and Fibrosis-4 index > 2.0 (n = 75), the liver stiffness values at baseline, EOT, and SVR24 were 9.6 (7.7-15.2), 9.2 (7.3-12.1), and 7.7 (6.3-10.1) kPa, respectively (P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). These results suggest that early improvement of liver stiffness starts during the administration of DAAs in patients who achieve SVR, and this effect is particularly pronounced in patients with progressive liver fibrosis. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  6. Antiviral prophylaxis during chemotherapy or immunosuppressive drug therapy to prevent HBV reactivation in patients with resolved HBV infection: a systematic review and meta-analysis.

    PubMed

    Su, Yi-Chia; Lin, Pei-Chin; Yu, Hsien-Chung; Wu, Chih-Chien

    2018-05-29

    Until recently, the role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation during immunosuppressive therapy or chemotherapy in patients with resolved HBV infection was unclear. The aim of the study reported here was to compare the efficacy of antiviral prophylaxis versus that of non-prophylaxis in resolved HBV-infected patients undergoing chemotherapy or immunosuppressive therapy. PubMed, the Cochrane library, and the ClinicalTrials.gov website were searched from inception until December 2017. Studies comparing reactivation in prophylaxis versus non-prophylaxis in patients undergoing immunosuppressive therapy or chemotherapy were included. The meta-analysis was performed to calculate the relative risk (RR) and the pooled estimates. A meta-analysis was conducted of 13 studies (2 randomized controlled trials [RCTs] and 11 cohort studies). The summary RR for HBV reactivation was 0.47 (95% confidence interval [CI] 0.13-1.69) for antiviral prophylaxis versus non-prophylaxis. Both of the RCTs included in the meta-analysis enrolled patients treated with rituximab. Subgroup analyses showed that the two RCTs ± high-quality cohort studies showed a decreased risk of HBV reactivation among the antiviral prophylaxis groups (RCT 1: RR 0.13, 95% CI 0.02-0.70; P = 0.02; RCT 2: 0.28, 95% CI 0.08-0.98; P = 0.05). Subgroup analyses further showed that the cohort studies did not support an association between the antiviral prophylaxis groups and HBV reactivation (RR 0.62, 95% CI 0.14-2.83; P = 0.54); adjusting for confounding factors, such as detectable anti-HBs antibodies, failed to produce a significant association (RR,0.29, 95% CI 0.07-1.28; P = 0.10). Our meta-analyses did not show an association between antiviral prophylaxis use and risk of HBV reactivation. As using only the RCTs ± high-quality cohort studies data rendered this association significant, clinicians can consider providing antiviral prophylaxis to patients with resolved

  7. Genetic and transcriptomic analyses provide new insights on the early antiviral response to VHSV in resistant and susceptible rainbow trout.

    PubMed

    Verrier, Eloi R; Genet, Carine; Laloë, Denis; Jaffrezic, Florence; Rau, Andrea; Esquerre, Diane; Dechamp, Nicolas; Ciobotaru, Céline; Hervet, Caroline; Krieg, Francine; Jouneau, Luc; Klopp, Christophe; Quillet, Edwige; Boudinot, Pierre

    2018-06-19

    The viral hemorrhagic septicemia virus (VHSV) is a major threat for salmonid farming and for wild fish populations worldwide. Previous studies have highlighted the importance of innate factors regulated by a major quantitative trait locus (QTL) for the natural resistance to waterborne VHSV infection in rainbow trout. The aim of this study was to analyze the early transcriptomic response to VHSV inoculation in cell lines derived from previously described resistant and susceptible homozygous isogenic lines of rainbow trout to obtain insights into the molecular mechanisms responsible for the resistance to the viral infection. We first confirmed the presence of the major QTL in a backcross involving a highly resistant fish isogenic line (B57) and a highly susceptible one (A22), and were able to define the confidence interval of the QTL and to identify its precise position. We extended the definition of the QTL since it controls not only resistance to waterborne infection but also the kinetics of mortality after intra-peritoneal injection. Deep sequencing of the transcriptome of B57 and A22 derived cell lines exposed to inactivated VHSV showed a stronger response to virus inoculation in the resistant background. In line with our previous observations, an early and strong induction of interferon and interferon-stimulated genes was correlated with the resistance to VHSV, highlighting the major role of innate immune factors in natural trout resistance to the virus. Interestingly, major factors of the antiviral innate immunity were much more expressed in naive B57 cells compared to naive A22 cells, which likely contributes to the ability of B57 to mount a fast antiviral response after viral infection. These observations were further extended by the identification of several innate immune-related genes localized close to the QTL area on the rainbow trout genome. Taken together, our results improve our knowledge in virus-host interactions in vertebrates and provide novel

  8. Interferon-based anti-viral therapy for hepatitis C virus infection after renal transplantation: an updated meta-analysis.

    PubMed

    Wei, Fang; Liu, Junying; Liu, Fen; Hu, Huaidong; Ren, Hong; Hu, Peng

    2014-01-01

    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. 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. 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. 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 tolerability, and reduce the liver-related morbidity and

  9. Evolution of animal and plant dicers: early parallel duplications and recurrent adaptation of antiviral RNA binding in plants.

    PubMed

    Mukherjee, Krishanu; Campos, Henry; Kolaczkowski, Bryan

    2013-03-01

    RNA interference (RNAi) is a eukaryotic molecular system that serves two primary functions: 1) gene regulation and 2) protection against selfish elements such as viruses and transposable DNA. Although the biochemistry of RNAi has been detailed in model organisms, very little is known about the broad-scale patterns and forces that have shaped RNAi evolution. Here, we provide a comprehensive evolutionary analysis of the Dicer protein family, which carries out the initial RNA recognition and processing steps in the RNAi pathway. We show that Dicer genes duplicated and diversified independently in early animal and plant evolution, coincident with the origins of multicellularity. We identify a strong signature of long-term protein-coding adaptation that has continually reshaped the RNA-binding pocket of the plant Dicer responsible for antiviral immunity, suggesting an evolutionary arms race with viral factors. We also identify key changes in Dicer domain architecture and sequence leading to specialization in either gene-regulatory or protective functions in animal and plant paralogs. As a whole, these results reveal a dynamic picture in which the evolution of Dicer function has driven elaboration of parallel RNAi functional pathways in animals and plants.

  10. Simplification of antiviral hepatitis C virus therapy to support expanded access in resource-limited settings.

    PubMed

    Ford, Nathan; Swan, Tracy; Beyer, Peter; Hirnschall, Gottfried; Easterbrook, Philippa; Wiktor, Stefan

    2014-11-01

    Currently, access to treatment for HCV is limited, with treatment rates lowest in the more resource-limited countries, including those countries with the highest prevalence. The use of oral DAAs has the potential to provide treatment at scale by offering opportunities to simplify drug regimens, laboratory requirements, and service delivery models. Key desirable characteristics of future HCV treatment regimens include high efficacy, tolerability, pan-genotype activity, short treatment duration, oral therapy, affordability, and availability as fixed-dose combination. Using such a regimen, HCV treatment delivery could be greatly simplified. Treatment could be initiated following confirmation of the presence of viraemia, with an initial assessment of the stage of liver disease. A combination DAA therapy that is safe and effective across genotypes could remove the need for genotyping and intermediary viral load assessments for response-guided therapy and reduce the need for adverse event monitoring. Simpler, safer, shorter therapy will also facilitate simplified service delivery, including task shifting, decentralization, and integration of treatment and care. The opportunity to scale up HCV treatment using such delivery approaches will depend on efforts needed to guarantee that the new DAAs are affordable in low-income settings. This will require the engagement of all stakeholders, ranging from the companies developing these new treatments, WHO and other international organizations, including procurement and funding mechanisms, governments and civil society. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  11. Changes in liver stiffness measurement using acoustic radiation force impulse elastography after antiviral therapy in patients with chronic hepatitis C.

    PubMed

    Chen, Sheng-Hung; Lai, Hsueh-Chou; Chiang, I-Ping; Su, Wen-Pang; Lin, Chia-Hsin; Kao, Jung-Ta; Chuang, Po-Heng; Hsu, Wei-Fan; Wang, Hung-Wei; Chen, Hung-Yao; Huang, Guan-Tarn; Peng, Cheng-Yuan

    2018-01-01

    To compare on-treatment and off-treatment parameters acquired using acoustic radiation force impulse elastography, the Fibrosis-4 (FIB-4) index, and aspartate aminotransferase-to-platelet ratio index (APRI) in patients with chronic hepatitis C (CHC). Patients received therapies based on pegylated interferon or direct-acting antiviral agents. The changes in paired patient parameters, including liver stiffness (LS) values, the FIB-4 index, and APRI, from baseline to sustained virologic response (SVR) visit (24 weeks after the end of treatment) were compared. Multiple regression models were used to identify significant factors that explained the correlations with LS, FIB-4, and APRI values and SVR. A total of 256 patients were included, of which 219 (85.5%) achieved SVR. The paired LS values declined significantly from baseline to SVR visit in all groups and subgroups except the nonresponder subgroup (n = 10). Body mass index (P = 0.0062) and baseline LS (P < 0.0001) were identified as independent factors that explained the LS declines. Likewise, the baseline FIB-4 (P < 0.0001) and APRI (P < 0.0001) values independently explained the declines in the FIB-4 index and APRI, respectively. Moreover, interleukin-28B polymorphisms, baseline LS, and rapid virologic response were identified as independent correlates with SVR. Paired LS measurements in patients treated for CHC exhibited significant declines comparable to those in FIB-4 and APRI values. These declines may have correlated with the resolution of necroinflammation. Baseline LS values predicted SVR.

  12. Liver stiffness predicts the response to direct-acting antiviral-based therapy against chronic hepatitis C in cirrhotic patients.

    PubMed

    Neukam, K; Morano-Amado, L E; Rivero-Juárez, A; Macías, J; Granados, R; Romero-Palacios, A; Márquez, M; Merino, D; Ortega, E; Alados-Arboledas, J C; Cucurull, J; Omar, M; Ryan-Murua, P; Pineda, J A

    2017-05-01

    The purpose of this investigation was to evaluate the impact of liver stiffness (LS) on the response to direct-acting antiviral (DAA)-based therapy against hepatitis C virus (HCV) infection in cirrhotic patients. Those patients included in two Spanish prospective cohorts of patients receiving therapy based on at least one DAA, who showed a baseline LS ≥ 12.5 kPa and who had reached the scheduled time point for sustained virological response evaluation 12 weeks after completing therapy (SVR12) were analysed. Pegylated interferon/ribavirin-based therapy plus an HCV NS3/4A protease inhibitor (PR-PI group) was administered to 198 subjects, while 146 received interferon-free regimens (IFN-free group). The numbers of patients with SVR12 according to an LS < 21 kPa versus ≥21 kPa were 59/99 (59.6%) versus 46/99 (46.5%) in the PR-PI group (p = 0.064) and 41/43 (95.3%) versus 90/103 (87.4%) in the IFN-free group (p = 0.232). Corresponding figures for the relapse rates in those who presented end-of-treatment response (ETR) were 3/62 (4.8%) versus 10/56 (17.9%, p = 0.024) and 1/42 (2.4%) versus 8/98 (8.2%, p = 0.278), respectively. In a multivariate analysis adjusted for age, sex and use of interferon, a baseline LS ≥ 21 kPa was identified as an independent predictor of relapse [adjusted odds ratio, AOR (95% confidence interval, CI): 4.228 (1.344-13.306); p = 0.014] in those patients with ETR. LS above 21 kPa is associated with higher rates of relapse to DAA-based therapy in HCV-infected patients with cirrhosis in clinical practice. LS could help us to tailor the duration and composition of DAA-based combinations in cirrhotic subjects, in order to minimise the likelihood of relapse.

  13. Ultrasensitive HCV RNA Quantification in Antiviral Triple Therapy: New Insight on Viral Clearance Dynamics and Treatment Outcome Predictors

    PubMed Central

    Garbuglia, Anna Rosa; Visco-Comandini, Ubaldo; Lionetti, Raffaella; Lapa, Daniele; Castiglione, Filippo; D’Offizi, Gianpiero; Taibi, Chiara; Montalbano, Marzia; Capobianchi, Maria Rosaria; Paci, Paola

    2016-01-01

    Objectives Identifying the predictive factors of Sustained Virological Response (SVR) represents an important challenge in new interferon-based DAA therapies. Here, we analyzed the kinetics of antiviral response associated with a triple drug regimen, and the association between negative residual viral load at different time points during treatment. Methods Twenty-three HCV genotype 1 (GT 1a n = 11; GT1b n = 12) infected patients were included in the study. Linear Discriminant Analysis (LDA) was used to establish possible association between HCV RNA values at days 1 and 4 from start of therapy and SVR. Principal component analysis (PCA) was applied to analyze the correlation between HCV RNA slope and SVR. A ultrasensitive (US) method was established to measure the residual HCV viral load in those samples which resulted “detected <12IU/ml” or undetectable with ABBOTT standard assay, and was retrospectively used on samples collected at different time points to establish its predictive power for SVR. Results According to LDA, there was no association between SVR and viral kinetics neither at time points earlier than 1 week (days 1 and 4) after therapy initiation nor later. The slopes were not relevant for classifying patients as SVR or no-SVR. No significant differences were observed in the median HCV RNA values at T0 among SVR and no-SVR patients. HCV RNA values with US protocol (LOD 1.2 IU/ml) after 1 month of therapy were considered; the area under the ROC curve was 0.70. Overall, PPV and NPV of undetectable HCV RNA with the US method for SVR was 100% and 46.7%, respectively; sensitivity and specificity were 38.4% and 100% respectively. Conclusion HCV RNA “not detected” by the US method after 1 month of treatment is predictive of SVR in first generation Protease inhibitor (PI)-based triple therapy. The US method could have clinical utility for advanced monitoring of virological response in new interferon based DAA combination regimens. PMID:27560794

  14. Viral eradication reduces both liver stiffness and steatosis in patients with chronic hepatitis C virus infection who received direct-acting anti-viral therapy.

    PubMed

    Tada, T; Kumada, T; Toyoda, H; Sone, Y; Takeshima, K; Ogawa, S; Goto, T; Wakahata, A; Nakashima, M; Nakamuta, M; Tanaka, J

    2018-04-01

    Whether direct-acting anti-viral therapy can reduce liver fibrosis and steatosis in patients with chronic hepatitis C virus (HCV) infection is unclear. To evaluate changes in liver stiffness and steatosis in patients with HCV who received direct-acting anti-viral therapy and achieved sustained virological response (SVR). A total of 198 patients infected with HCV genotype 1 or 2 who achieved SVR after direct-acting anti-viral therapy were analysed. Liver stiffness as evaluated by magnetic resonance elastography, steatosis as evaluated by magnetic resonance imaging-determined proton density fat fraction (PDFF), insulin resistance, and laboratory data were assessed before treatment (baseline) and at 24 weeks after the end of treatment (SVR24). Alanine aminotransferase and homeostatic model assessment-insulin resistance levels decreased significantly from baseline to SVR24. Conversely, platelet count, which is inversely associated with liver fibrosis, increased significantly from baseline to SVR24. In patients with high triglyceride levels (≥150 mg/dL), triglyceride levels significantly decreased from baseline to SVR24 (P = 0.004). The median (interquartile range) liver stiffness values at baseline and SVR24 were 3.10 (2.70-4.18) kPa and 2.80 (2.40-3.77) kPa respectively (P < 0.001). The PDFF values at baseline and SVR 24 were 2.4 (1.7-3.4)% and 1.9 (1.3-2.8)% respectively (P < 0.001). In addition, 68% (19/28) of patients with fatty liver at baseline (PDFF ≥5.2%; n = 28) no longer had fatty liver (PDFF <5.2%) at SVR24. Viral eradication reduces both liver stiffness and steatosis in patients with chronic HCV who received direct-acting anti-viral therapy (UMIN000017020). © 2018 John Wiley & Sons Ltd.

  15. Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy.

    PubMed

    Jacobson, Ira M; Washington, Mary K; Buti, Maria; Thompson, Alexander; Afdhal, Nezam; Flisiak, Robert; Akarca, Ulus Salih; Tchernev, Konstantin G; Flaherty, John F; Aguilar Schall, Raul; Myers, Robert P; Subramanian, G Mani; McHutchison, John G; Younossi, Zobair; Marcellin, Patrick; Patel, Keyur

    2017-07-01

    Despite complete suppression of viral DNA with antiviral agents, in some patients with chronic hepatitis B (CHB), serum levels of alanine aminotransferase (ALT) do not normalize. We investigated factors associated with persistent increases in ALT level in patients with CHB given long-term tenofovir disoproxil fumarate. We analyzed data from 471 hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB participating in 2 phase 3 trials. We identified patients with an increased level of ALT (above the upper limit of normal range) after 5 years (240 weeks) of tenofovir disoproxil fumarate therapy. We analyzed findings from liver biopsy specimens collected from 467 patients (99%) at baseline and 339 patients (72%) at year 5 of treatment; biopsy specimens were evaluated by an independent pathologist. We performed stepwise, forward, multivariate regression analyses of specified baseline characteristics and on-treatment response parameters to identify factors associated with persistent increases in ALT level. Of the 471 patients, 87 (18%) still had an increased ALT level at year 5 of treatment. Factors associated significantly with a persistent increase in ALT level were a steatosis score of 5% or greater (grade 1 or more) at baseline (odds ratio [OR], 2.236; 95% confidence interval [CI], 1.031-4.852; P = .042) and at year 5 (OR, 3.392; 95% CI, 1.560 ≥ 7.375; P = .002), HBeAg seropositivity at baseline (OR, 3.297; 95% CI, 1.653-6.576; P < .001), and age 40 years or older (OR, 2.099; 95% CI, 1.014-4.342; P = .046). Of the 42 HBeAg-positive patients with steatosis at baseline, 21 (50%) had an increased ALT level at year 5 of treatment. Patients with persistent increases in ALT level were more likely to have an increase in steatosis at year 5 than those with a normal ALT level. HBeAg seropositivity and hepatic steatosis contribute to persistent increases in ALT level in patients with CHB receiving suppressive antiviral treatment. Clinical

  16. Six-week follow-up after HIV-1 exposure: a position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy.

    PubMed

    Gaines, Hans; Albert, Jan; Axelsson, Maria; Berglund, Torsten; Gisslén, Magnus; Sönnerborg, Anders; Blaxhult, Anders; Bogdanovic, Gordana; Brytting, Maria; Carlander, Christina; Flamholc, Leo; Follin, Per; Haggar, Axana; Hagstam, Per; Johansson, Marcus; Navér, Lars; Persson Blom, Jenny; Samuelson, Agneta; Ström, Helena; Sundqvist, Martin; Svedhem Johansson, Veronica; Tegmark Wisell, Karin; Tegnell, Anders; Thorstensson, Rigmor

    2016-02-01

    In 2014 the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy (RAV) conducted a review and analysis of the state of knowledge on the duration of follow-up after exposure to human immunodeficiency virus (HIV). Up until then a follow-up of 12 weeks after exposure had been recommended, but improved tests and new information on early diagnosis motivated a re-evaluation of the national recommendations by experts representing infectious diseases and microbiology, county medical officers, the RAV, the Public Health Agency, and other national authorities. Based on the current state of knowledge the Public Health Agency of Sweden and the RAV recommend, starting in April 2015, a follow-up period of 6 weeks after possible HIV-1 exposure, if HIV testing is performed using laboratory-based combination tests detecting both HIV antibody and antigen. If point-of-care rapid HIV tests are used, a follow-up period of 8 weeks is recommended, because currently available rapid tests have insufficient sensitivity for detection of HIV-1 antigen. A follow-up period of 12 weeks is recommended after a possible exposure for HIV-2, since presently used assays do not include HIV-2 antigens and only limited information is available on the development of HIV antibodies during early HIV-2 infection. If pre- or post-exposure prophylaxis is administered, the follow-up period is recommended to begin after completion of prophylaxis. Even if infection cannot be reliably excluded before the end of the recommended follow-up period, HIV testing should be performed at first contact for persons who seek such testing.

  17. Anti-E1E2 antibodies status prior therapy favors direct-acting antiviral treatment efficacy.

    PubMed

    Virlogeux, Victor; Berthillon, Pascale; Bordes, Isabelle; Larrat, Sylvie; Crouy, Stéphanie; Scholtès, Caroline; Pradat, Pierre; Maynard, Marianne; Zoulim, Fabien; Leroy, Vincent; Chemin, Isabelle; Trépo, Christian; Petit, Marie-Anne

    2018-03-15

    Presence of anti-E1E2 antibodies was previously associated with spontaneous cure of hepatitis C virus (HCV) and predictive before treatment of a sustained virological response (SVR) to bi- or tri-therapy in naïve or experienced patients, regardless of HCV genotype. We investigated the impact of anti-E1E2 seroprevalence at baseline on treatment response in patients receiving direct-acting antiviral (DAA) therapy. We screened anti-E1E2 antibodies by ELISA in serum samples collected at treatment initiation for two groups of patients: 59 with SVR at the end of DAA treatment and 44 relapsers after DAA treatment. Nineteen patients received a combination of ribavirin (RBV) or PEG-interferon/ribavirin with sofosbuvir or daclatasvir and others received interferon-free treatment with DAA±RBV. HCV viral load was measured at different time points during treatment in a subgroup of patients. A significant association was observed between presence of anti-E1E2 and HCV viral load<6log10 prior treatment. Among patients with anti-E1E2 at baseline, 70% achieved SVR whereas among patients without anti-E1E2, only 45% achieved SVR. Conversely, 66% of patients experiencing DAA-failure were anti-E1E2 negative at baseline. In the multivariate analysis, presence of anti-E1E2 was significantly associated with SVR after adjustment on potential cofounders such as age, sex, fibrosis stage, prior HCV treatment and alanine aminotransferase (ALT) level. The presence of anti-E1E2 at treatment initiation is a predictive factor of SVR among patients treated with DAA and more likely among patients with low initial HCV viral load (<6log10). Absence of anti-E1E2 at baseline could predict DAA-treatment failure. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  18. Prolonged detection of herpes simplex virus type 2 (HSV-2) DNA in cerebrospinal fluid despite antiviral therapy in a patient with HSV-2-associated radiculitis.

    PubMed

    Ganzenmueller, Tina; Karaguelle, Deniz; Schmitt, Corinna; Puppe, Wolfram; Stachan-Kunstyr, Rita; Bronzlik, Paul; Sauerbrei, Andreas; Wegner, Florian; Heim, Albert

    2012-01-01

    Herpes simplex virus type 2 (HSV-2) can cause radiculo-myelitis as a neurological manifestation. We report a case of ongoing HSV-2 DNA positivity in the cerebrospinal fluid (CSF) of at least eight weeks under antiviral therapy with acyclovir in a highly immunocompromised hemato-oncologic patient with HSV-2-associated radiculitis. Upon admission, the patient presented with pain, leg paresis, and urinary incontinence, as well as pleocytosis in the CSF. Quantitative real-time PCR of the CSF at day 3 after admission revealed HSV-2 with a concentration of 2.0×10(5) copies/ml and treatment with acyclovir intravenously and prednisolone by mouth was started. Clinical symptoms resolved almost completely after approximately 3 weeks of antiviral therapy. However, CSF samples of day 12, 19, 26, 33, 39, 48 and 54 after admission showed a slow decline of HSV-2 DNA concentrations. HSV-2 DNA was still detectable (1.6×10(4) copies/ml) at day 54 after admission. Genotypic resistance testing showed, as far as available, no mutations indicative for acyclovir resistance. Since an increasing specific antibody index for HSV was observed, we speculate that the prolonged detectability of HSV-2 DNA in the CSF might not necessarily indicate ongoing viral replication but neutralized virus. Other hypotheses and the consequences on treatment are discussed. To our knowledge this is the first report about the long-term viral load kinetics of HSV-2 in the CSF of a patient with radiculitis under antiviral therapy, highlighting the need for further studies on HSV DNA kinetics in the CSF and their significance for an appropriate antiviral treatment.

  19. A Kinome-Wide Small Interfering RNA Screen Identifies Proviral and Antiviral Host Factors in Severe Acute Respiratory Syndrome Coronavirus Replication, Including Double-Stranded RNA-Activated Protein Kinase and Early Secretory Pathway Proteins

    PubMed Central

    de Wilde, Adriaan H.; Wannee, Kazimier F.; Scholte, Florine E. M.; Goeman, Jelle J.; ten Dijke, Peter; Snijder, Eric J.

    2015-01-01

    ABSTRACT To identify host factors relevant for severe acute respiratory syndrome-coronavirus (SARS-CoV) replication, we performed a small interfering RNA (siRNA) library screen targeting the human kinome. Protein kinases are key regulators of many cellular functions, and the systematic knockdown of their expression should provide a broad perspective on factors and pathways promoting or antagonizing coronavirus replication. In addition to 40 proteins that promote SARS-CoV replication, our study identified 90 factors exhibiting an antiviral effect. Pathway analysis grouped subsets of these factors in specific cellular processes, including the innate immune response and the metabolism of complex lipids, which appear to play a role in SARS-CoV infection. Several factors were selected for in-depth validation in follow-up experiments. In cells depleted for the β2 subunit of the coatomer protein complex (COPB2), the strongest proviral hit, we observed reduced SARS-CoV protein expression and a >2-log reduction in virus yield. Knockdown of the COPB2-related proteins COPB1 and Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) also suggested that COPI-coated vesicles and/or the early secretory pathway are important for SARS-CoV replication. Depletion of the antiviral double-stranded RNA-activated protein kinase (PKR) enhanced virus replication in the primary screen, and validation experiments confirmed increased SARS-CoV protein expression and virus production upon PKR depletion. In addition, cyclin-dependent kinase 6 (CDK6) was identified as a novel antiviral host factor in SARS-CoV replication. The inventory of pro- and antiviral host factors and pathways described here substantiates and expands our understanding of SARS-CoV replication and may contribute to the identification of novel targets for antiviral therapy. IMPORTANCE Replication of all viruses, including SARS-CoV, depends on and is influenced by cellular pathways. Although

  20. Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C.

    PubMed

    Virlogeux, Victor; Pradat, Pierre; Hartig-Lavie, Kerstin; Bailly, François; Maynard, Marianne; Ouziel, Guillaume; Poinsot, Domitille; Lebossé, Fanny; Ecochard, Marie; Radenne, Sylvie; Benmakhlouf, Samir; Koffi, Joseph; Lack, Philippe; Scholtes, Caroline; Uhres, Anne-Claire; Ducerf, Christian; Mabrut, Jean-Yves; Rode, Agnès; Levrero, Massimo; Combet, Christophe; Merle, Philippe; Zoulim, Fabien

    2017-08-01

    Arrival of direct-acting antiviral agents against hepatitis C virus with high-sustained virological response rates and very few side effects has drastically changed the management of hepatitis C virus infection. The impact of direct-acting antiviral exposure on hepatocellular carcinoma recurrence after a first remission in patients with advanced fibrosis remains to be clarified. 68 consecutive hepatitis C virus patients with a first hepatocellular carcinoma diagnosis and under remission, subsequently treated or not with a direct-acting antiviral combination, were included. Clinical, biological and virological data were collected at first hepatocellular carcinoma diagnosis, at remission and during the surveillance period. All patients were cirrhotic. Median age was 62 years and 76% of patients were male. Twenty-three patients (34%) were treated with direct-acting antivirals and 96% of them achieved sustained virological response. Median time between hepatocellular carcinoma remission and direct-acting antivirals initiation was 7.2 months (IQR: 3.6-13.5; range: 0.3-71.4) and median time between direct-acting antivirals start and hepatocellular carcinoma recurrence was 13.0 months (IQR: 9.2-19.6; range: 3.0-24.7). Recurrence rate was 1.7/100 person-months among treated patients vs 4.2/100 person-months among untreated patients (P=.008). In multivariate survival analysis, the hazard ratio for hepatocellular carcinoma recurrence after direct-acting antivirals exposure was 0.24 (95% confidence interval: 0.10-0.55; P<.001). Hepatocellular carcinoma recurrence rate was significantly lower among patients treated with direct-acting antivirals compared with untreated patients. Given the potential impact of our observation, large-scale prospective cohort studies are needed to confirm these results. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Impact of antiviral prophylaxis in adults Epstein-Barr Virus-seronegative kidney recipients on early and late post-transplantation lymphoproliferative disorder onset: a retrospective cohort study.

    PubMed

    Ville, Simon; Imbert-Marcille, Berthe-Marie; Coste-Burel, Marianne; Garandeau, Claire; Meurette, Aurélie; Cantarovitch, Diego; Giral, Magali; Hourmant, Maryvonne; Blancho, Gilles; Dantal, Jacques

    2018-05-01

    Post-transplantation lymphoproliferative disorder (PTLD) pathogenesis is related to EBV infection. Mismatch with the donor (EBV D+/R-) is the main risk factor for both early PTLD (<1 year post-transplantation) and late (>1 year). In these at-risk patients, the role of antiviral prophylaxis for preventing PTLD remains controversial. We analyzed the impact of antiviral drugs given to prevent CMV disease in a monocentric retrospective cohort of 73 adult kidney or kidney-pancreas EBV-seronegative recipients, transplanted between 01/01/2000 and 01/01/2016. Thirty-seven (50.7%, prophylaxis group) received (val-)aciclovir or (val-)ganciclovir for 3-6 months and 36 (49.3%, no-prophylaxis group) received no-prophylaxis. Mean follow-up was 69 ± 7.2 months in the prophylaxis group and 91 ± 10.3 months in the no-prophylaxis group. Monitoring of EBV PCR revealed that prophylaxis delayed primary infection at 100 days (43% vs. 84%, P = 0.02). Early PTLD incidence was not different between groups (4/37 vs. 4/36, P = 0.99). Concerning late events, EBV-related neoplasia incidence was significantly lower in treated patients among whom no cases were observed, while in the no-prophylaxis group 6 cases were reported (P = 0.02). Despite a weak level of evidence our study suggests that antiviral prophylaxis could prevent late onset PTLD. © 2017 Steunstichting ESOT.

  2. Antiviral T Cells for Adenovirus in the Pretransplant Period: A Bridge Therapy for Severe Combined Immunodeficiency.

    PubMed

    Miller, Holly K; Hanley, Patrick J; Lang, Haili; Lazarski, Christopher A; Chorvinsky, Elizabeth A; McCormack, Sarah; Roesch, Lauren; Albihani, Shuroug; Dean, Marcus; Hoq, Fahmida; Adams, Roberta H; Bollard, Catherine M; Keller, Michael D

    2018-05-09

    Viral infections can be life threatening in patients with severe combined immunodeficiency (SCID) and other forms of profound primary immunodeficiency disorders both before and after hematopoietic stem cell transplantation (HSCT). Adoptive immunotherapy with virus-specific T cells (VSTs) has been utilized in many patients in the setting of HSCT, but has very rarely been attempted for treatment of viral infections before HSCT. Here we describe the use of VSTs in an infant with RAG1 SCID who had developed disseminated adenovirus which failed to improve on cidofovir. Adenovirus cleared following 2 doses of VSTs and marrow infusion from a matched unrelated donor, without incidence of graft versus host disease. T cell receptor-b sequencing demonstrated expansion of adenovirus-specific T cell fraction of the VSTs, suggesting that infusion facilitated viral clearance. This report suggests that VSTs are likely safe in the pre-HSCT period, and may be a useful bridge therapy for infants with SCID and persistent viral infections. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  3. Risk of HIV transmission from patients on antiretroviral therapy: a position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy.

    PubMed

    Albert, Jan; Berglund, Torsten; Gisslén, Magnus; Gröön, Peter; Sönnerborg, Anders; Tegnell, Anders; Alexandersson, Anders; Berggren, Ingela; Blaxhult, Anders; Brytting, Maria; Carlander, Christina; Carlson, Johan; Flamholc, Leo; Follin, Per; Haggar, Axana; Hansdotter, Frida; Josephson, Filip; Karlström, Olle; Liljeros, Fredrik; Navér, Lars; Pettersson, Karin; Johansson, Veronica Svedhem; Svennerholm, Bo; Tunbäck, Petra; Widgren, Katarina

    2014-10-01

    The modern medical treatment of HIV with antiretroviral therapy (ART) has drastically reduced the morbidity and mortality in patients infected with this virus. ART has also been shown to reduce the transmission risk from individual patients as well as the spread of the infection at the population level. This position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy is based on a workshop organized in the fall of 2012. It summarizes the latest research and knowledge on the risk of HIV transmission from patients on ART, with a focus on the risk of sexual transmission. The risk of transmission via shared injection equipment among intravenous drug users is also examined, as is the risk of mother-to-child transmission. Based on current knowledge, the risk of transmission through vaginal or anal intercourse involving the use of a condom has been judged to be minimal, provided that the person infected with HIV fulfils the criteria for effective ART. This probably also applies to unprotected intercourse, provided that no other sexually transmitted infections are present, although it is not currently possible to fully support this conclusion with direct scientific evidence. ART is judged to markedly reduce the risk of blood-borne transmission between people who share injection equipment. Finally, the risk of transmission from mother to child is very low, provided that ART is started well in advance of delivery.

  4. Risk of HIV transmission from patients on antiretroviral therapy: A position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy

    PubMed Central

    Berglund, Torsten; Gisslén, Magnus; Gröön, Peter; Sönnerborg, Anders; Tegnell, Anders; Alexandersson, Anders; Berggren, Ingela; Blaxhult, Anders; Brytting, Maria; Carlander, Christina; Carlson, Johan; Flamholc, Leo; Follin, Per; Haggar, Axana; Hansdotter, Frida; Josephson, Filip; Karlström, Olle; Liljeros, Fredrik; Navér, Lars; Pettersson, Karin; Johansson, Veronica Svedhem; Svennerholm, Bo; Tunbäck, Petra; Widgren, Katarina

    2014-01-01

    The modern medical treatment of HIV with antiretroviral therapy (ART) has drastically reduced the morbidity and mortality in patients infected with this virus. ART has also been shown to reduce the transmission risk from individual patients as well as the spread of the infection at the population level. This position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy is based on a workshop organized in the fall of 2012. It summarizes the latest research and knowledge on the risk of HIV transmission from patients on ART, with a focus on the risk of sexual transmission. The risk of transmission via shared injection equipment among intravenous drug users is also examined, as is the risk of mother-to-child transmission. Based on current knowledge, the risk of transmission through vaginal or anal intercourse involving the use of a condom has been judged to be minimal, provided that the person infected with HIV fulfils the criteria for effective ART. This probably also applies to unprotected intercourse, provided that no other sexually transmitted infections are present, although it is not currently possible to fully support this conclusion with direct scientific evidence. ART is judged to markedly reduce the risk of blood-borne transmission between people who share injection equipment. Finally, the risk of transmission from mother to child is very low, provided that ART is started well in advance of delivery. PMID:25073537

  5. Targeting HIV-1 gp41-induced fusion and pathogenesis for anti-viral therapy.

    PubMed

    Garg, Himanshu; Viard, Mathias; Jacobs, Amy; Blumenthal, Robert

    2011-12-01

    HIV gp41 is a metastable protein whose native conformation is maintained in the form of a heterodimer with gp120. The non-covalently associated gp41/gp120 complex forms a trimer on the virus surface. As gp120 engages with HIV's receptor, CD4, and coreceptor, CXCR4 or CCR5, gp41 undergoes several conformational changes resulting in fusion between the viral and cellular membranes. Several lipophilic and amphiphilic domains have been shown to be critical in that process. While the obvious function of gp41 in viral entry is well-established its role in cellular membrane fusion and the link with pathogenesis are only now beginning to appear. Recent targeting of gp41 via fusion inhibitors has revealed an important role of this protein not only in viral entry but also in bystander apoptosis and HIV pathogenesis. Studies by our group and others have shown that the phenomenon of gp41-mediated hemifusion initiates apoptosis in bystander cells and correlates with virus pathogenesis. More interestingly, recent clinical evidence suggests that gp41 mutants arising after Enfuvirtide therapy are associated with CD4 cell increase and immunological benefits. This has in turn been correlated to a decrease in bystander apoptosis in our in vitro as well as in vivo assays. Although a great deal of work has been done to unravel HIV-1 gp41-mediated fusion mechanisms, the factors that regulate gp41-mediated fusion versus hemifusion and the mechanism by which hemifusion initiates bystander apoptosis are not fully understood. Further insight into these issues will open new avenues for drug development making gp41 a critical anti-HIV target both for neutralization and virus attenuation.

  6. Antiviral agents: structural basis of action and rational design.

    PubMed

    Menéndez-Arias, Luis; Gago, Federico

    2013-01-01

    During the last 30 years, significant progress has been made in the development of novel antiviral drugs, mainly crystallizing in the establishment of potent antiretroviral therapies and the approval of drugs inhibiting hepatitis C virus replication. Although major targets of antiviral intervention involve intracellular processes required for the synthesis of viral proteins and nucleic acids, a number of inhibitors blocking virus assembly, budding, maturation, entry or uncoating act on virions or viral capsids. In this review, we focus on the drug discovery process while presenting the currently used methodologies to identify novel antiviral drugs by using a computer-based approach. We provide examples illustrating structure-based antiviral drug development, specifically neuraminidase inhibitors against influenza virus (e.g. oseltamivir and zanamivir) and human immunodeficiency virus type 1 protease inhibitors (i.e. the development of darunavir from early peptidomimetic compounds such as saquinavir). A number of drugs in preclinical development acting against picornaviruses, hepatitis B virus and human immunodeficiency virus and their mechanism of action are presented to show how viral capsids can be exploited as targets of antiviral therapy.

  7. Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients With Chronic Hepatitis C: A Systematic Review and Meta-analysis.

    PubMed

    Singh, Siddharth; Facciorusso, Antonio; Loomba, Rohit; Falck-Ytter, Yngve T

    2018-01-01

    We performed a systematic review and meta-analysis to estimate the decrease in liver stiffness, measured by vibration-controlled transient elastrography (VCTE), in patients with hepatitis C virus infection who achieved a sustained virologic response (SVR). We searched the literature through October 2016 for observational studies or randomized controlled trials of adults with hepatitis C virus infection who received antiviral therapy (either direct-acting antiviral agents or interferon-based therapies), underwent liver stiffness measurement using VCTE before starting therapy, and had at least 1 follow-up VCTE after completion of therapy; studies also provided data on mean or median liver stiffness measurements for patients who did and did not achieve an SVR. We identified 24 studies, and estimated weighted mean difference (and 95% confidence interval) in liver stiffness in patients with versus without SVR using random-effects meta-analysis. In patients who achieved SVR, liver stiffness decreased by 2.4 kPa at the end of therapy (95% CI, -1.7 to -3.0), by 3.1 kPa 1-6 months after therapy (95% CI, -1.6 to -4.7), by 3.2 kPa 6-12 months after therapy (90% CI, -2.6 to -3.9), and 4.1 kPa 12 months or more after therapy (95% CI, -3.3 to -4.9) (median decrease, 28.2%; interquartile range, 21.8-34.8). In contrast, there was no significant change in liver stiffness in patients who did not achieve an SVR (at 6-12 months after therapy, decrease of 0.6 kPa; 95% CI, -1.7 to 0.5). Decreases in liver stiffness were significantly greater in patients treated with direct-acting antiviral agents than with interferon-based therapy (decrease of 4.5 kPa vs decrease of 2.6 kPa; P = .03), cirrhosis at baseline (decrease of 5.1 kPa vs decrease of 2.8 kPa in patients with no cirrhosis; P = .02), or high pretreatment levels of alanine aminotransferase (P < .01). Among patients with baseline liver stiffness >9.5 kPa, 47% (95% CI, 27%-68%) achieved posttreatment liver stiffness of <9

  8. Contact tracing and antiviral prophylaxis in the early stages of a pandemic: the probability of a major outbreak.

    PubMed

    Ross, Joshua V; Black, Andrew J

    2015-09-01

    Antiviral prophylaxis forms a significant component of health management plans for many countries around the world. A number of studies have shown that the delays typically encountered in distributing these antivirals to households, following the first infectious case, can result in their efficacy being severely reduced. Here, we investigate the use of contact tracing as a method to reduce the delays and hence mitigate the reduction in efficacy of antivirals. We assess the usefulness of contact tracing in terms of the probability of a major outbreak. It is found, with parameter distributions appropriate to the 2009 H1N1 pandemic and distributions reflecting commonly experienced delays, that standard contact tracing renders an outbreak impossible approximately one in five times compared with approximately one in ten times in its absence. A contact-tracing efficiency of 50% would see further improvements with an outbreak being impossible approximately one in four times, and a reduction of the median probability of a major outbreak from 0.41 to below 0.27. © The authors 2014. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

  9. Final Report of Unmet Needs of Interferon-Based Therapy for Chronic Hepatitis C in Korea: Basis for Moving into the Direct-Acting Antiviral Era

    PubMed Central

    Jang, Eun Sun; Kim, Young Seok; Kim, Kyung-Ah; Lee, Youn Jae; Chung, Woo Jin; Kim, In Hee; Lee, Byung Seok; Jeong, Sook-Hyang

    2017-01-01

    Background/Aims To evaluate the era of direct acting antivirals (DAAs), we must understand the treatment patterns and outcomes of interferon-based therapy for hepatitis C virus (HCV) infection. We aimed to elucidate the treatment rate, factors affecting treatment decisions, and efficacy of interferon-based therapy in a real-world setting. Methods This nationwide cohort study included 1,191 newly diagnosed patients with chronic HCV infection at seven tertiary hospitals in South Korea. Subjects were followed retrospectively until March 2015, which was just before the approval of DAA therapy. Results In total, 48.2% and 49.3% of the patients had HCV genotypes 1 and 2, respectively. Interferon-based therapy was initiated in 541 patients (45.4%). The major reasons for no treatment included ineligibility (18.9%), concern about adverse events (22.3%), cost (21.5%), and an age >75 years (19.5%). Interferon-based therapy was discontinued (18.5%) mainly due to adverse events (n=66). The intent-to-treat analysis found that the sustained virologic response (SVR) rate was 58.3% in genotype 1 patients and 74.7% in non-genotype 1 patients. Conclusions Approximately one-third of newly diagnosed HCV patients in South Korea received interferon-based therapy and showed a suboptimal SVR rate. Diagnosis of patients at younger ages and with a less advanced liver status and reducing the DAA therapy cost may fulfill unmet needs. PMID:28506027

  10. Antiviral Functions of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific IgG Antibodies: Effects of Antiretroviral Therapy and Implications for Therapeutic HIV-1 Vaccine Design

    PubMed Central

    French, Martyn A.; Tjiam, M. Christian; Abudulai, Laila N.; Fernandez, Sonia

    2017-01-01

    Contemporary antiretroviral therapy (ART) is effective and tolerable for long periods of time but cannot eradicate human immunodeficiency virus type 1 (HIV-1) infection by either elimination of viral reservoirs or enhancement of HIV-1-specific immune responses. Boosting “protective” HIV-1-specific immune responses by active or passive immunization will therefore be necessary to control or eradicate HIV-1 infection and is currently the topic of intense investigation. Recently reported studies conducted in HIV patients and non-human primate (NHP) models of HIV-1 infection suggest that HIV-1-specific IgG antibody responses may contribute to the control of HIV-1 infection. However, production of IgG antibodies with virus neutralizing activity by vaccination remains problematic and while vaccine-induced natural killer cell-activating IgG antibodies have been shown to prevent the acquisition of HIV-1 infection, they may not be sufficient to control or eradicate established HIV-1 infection. It is, therefore, important to consider other functional characteristics of IgG antibody responses. IgG antibodies to viruses also mediate opsonophagocytic antibody responses against virions and capsids that enhance the function of phagocytic cells playing critical roles in antiviral immune responses, particularly conventional dendritic cells and plasmacytoid dendritic cells. Emerging evidence suggests that these antibody functions might contribute to the control of HIV-1 infection. In addition, IgG antibodies contribute to the intracellular degradation of viruses via binding to the cytosolic fragment crystallizable (Fc) receptor tripartite motif containing-21 (TRIM21). The functional activity of an IgG antibody response is influenced by the IgG subclass content, which affects binding to antigens and to Fcγ receptors on phagocytic cells and to TRIM21. The IgG subclass content and avidity of IgG antibodies is determined by germinal center (GC) reactions in follicles of lymphoid

  11. Antiviral Agents Added to Corticosteroids for Early Treatment of Adults With Acute Idiopathic Facial Nerve Paralysis (Bell Palsy).

    PubMed

    Sullivan, Frank; Daly, Fergus; Gagyor, Ildiko

    Compared with oral corticosteroids alone, are oral antiviral drugs associated with improved outcomes when combined with oral corticosteroids in patients presenting within 72 hours of the onset of Bell palsy? Compared with oral corticosteroids alone, the addition of acyclovir, valacyclovir, or famcyclovir to oral corticosteroids for treatment of Bell palsy was associated with a higher proportion of people who recovered at 3- to 12-month follow-up. The quality of evidence is limited by heterogeneity, imprecision of the result estimates, and risk of bias.

  12. Antiviral therapy in hepatitis B virus-infected children with immune-tolerant characteristics: A pilot open-label randomized study.

    PubMed

    Zhu, Shishu; Zhang, Hongfei; Dong, Yi; Wang, Limin; Xu, Zhiqiang; Liu, Weiwei; Gan, Yu; Tang, Hongmei; Chen, Dawei; Wang, Fuchuan; Zhao, Pan

    2018-06-01

    Chronic infection with hepatitis B virus (HBV) in children is a serious health problem worldwide. How to treat children with immune-tolerant chronic hepatitis B infection, commonly characterized by hepatitis B e antigen (HBeAg) positivity, high viral load, normal or mildly elevated alanine aminotransferase and no or minimal inflammation in liver histology, remains unresolved. This trial aims to study the benefits of antiviral therapy in children with these characteristics. This is a pilot open-label randomized controlled study. From May 2014 to April 2015, 69 treatment-naive chronically HBV-infected children, aged 1 to 16 years, who had immune-tolerant characteristics were recruited to this trial and randomly assigned, in a 2:1 ratio, to treatment group and control group. Patients in the treatment group received either interferon-α (IFN) monotherapy or consecutively received IFN monotherapy, combination therapy of IFN and lamivudine (LAM), and LAM therapy alone. All patients were observed until week 96. At baseline, epidemiological, biochemical, serological, virological and histological indices were consistent across the treatment and control groups. Of the 46 patients in the treatment group, 73.91% had undetectable serum HBV DNA, 32.61% achieved HBeAg seroconversion and 21.74% lost hepatitis B surface antigen (HBsAg) at the endpoint. No LAM resistance emerged at week 96. In the control group, only one (4.35%) patient underwent spontaneous HBeAg seroconversion and had undetectable serum HBV DNA during observation, and moreover, none developed HBsAg clearance. For all patients, no serious adverse events were observed. Antiviral treatment with a sequential combination of IFN and LAM resulted in a significant improvement in the rates of undetectable serum HBV DNA, HBeAg seroconversion and HBsAg loss in children with chronic HBV infection and immune-tolerant characteristics. There is a lack of data regarding treatment of immune-tolerant chronic hepatitis B (CHB). It

  13. Comparison of Three Different Sensitive Assays for Hepatitis B Virus DNA in Monitoring of Responses to Antiviral Therapy

    PubMed Central

    Chan, Henry L. Y.; Leung, Nancy W. Y.; Lau, Tracy C. M.; Wong, May L.; Sung, Joseph J. Y.

    2000-01-01

    The aim of our study was to compare the performances of two new hepatitis B virus (HBV) DNA assays, a cross-linking assay (NAXCOR) and a hybrid-capture amplification assay (Digene), versus the widely used branched-DNA (bDNA) assay (Chiron) in the monitoring of HBV DNA levels during antiviral treatment. Serial serum samples from 12 chronically HBV infected patients undergoing a phase II trial of an antiviral drug, 2′,3′-dideoxy-5-fluoro-3′-thiacytidine (FTC), were studied. A total of 96 serum samples were tested for HBV DNA using the cross-linking, hybrid-capture amplification, and bDNA assays. In the comparison of the cross-linking and bDNA assays, concordant results were found in 77 (80.3%) samples, no significant difference was found between the median log10 HBV DNA levels (6.66 versus 7.17 meq/ml), and the results of the two assays were closely correlated (r = 0.95). In the comparison of the hybrid-capture amplification and bDNA assays, concordant results were found in 79 (82.3%) samples, no significant difference was found between the median log10 HBV DNA levels (6.98 versus 6.99 meq/ml), and the results of the two assays were closely correlated (r = 0.99). Six (6.3%) samples by the cross-linking assay and 10 (10.4%) samples by the bDNA assay required retesting because of unacceptably high within-run coefficients of variance. No sample required retesting in the hybrid-capture amplification assay according to the internal validation. In conclusion, the cross-linking and hybrid-capture amplification assays were as sensitive as the bDNA assay for HBV DNA detection and can be recommended for monitoring of HBV DNA levels during antiviral treatment. PMID:10970358

  14. Significant renoprotective effect of telbivudine during preemptive antiviral therapy in advanced liver cancer patients receiving cisplatin-based chemotherapy: a case-control study.

    PubMed

    Lin, Chih-Lang; Chien, Rong-Nan; Yeh, Charisse; Hsu, Chao-Wei; Chang, Ming-Ling; Chen, Yi-Cheng; Yeh, Chau-Ting

    2014-12-01

    Cisplatin is a known nephrotoxic agent requiring vigorous hydration before use. However, aggressive hydration could be life-threatening. Therefore, in cirrhotic patients with advanced hepatocellular carcinoma (HCC) under cisplatin-based chemotherapy, the risk of nephrotoxicity increased. Because previous studies showed that long-term telbivudine treatment improved renal function in chronic hepatitis B virus (HBV) infected patients, we conducted a case-control study to evaluate the clinical outcome of telbivudine preemptive therapy in HBV-related advanced HCC patients treated by combination chemotherapy comprising 5-fluorouracil, mitoxantrone and cisplatin (FMP). From June 2007 to March 2012, 60 patients with HBV-related advanced HCC, all receiving the same FMP chemotherapy protocol, were enrolled. Of them, 20 did not receive any antiviral therapy, whereas the remaining 40 patients (sex and age matched) received telbivudine preemptive therapy. Progressive decrease of aminotransferase levels (p < 0.05) and progressive increase of viral clearance rates (p < 0.001) were found in telbivudine-treated group. No drug resistance developed during the course of treatment. When compared with non-antiviral-treated patients, a significantly higher post-therapeutic estimated glomerular filtration rate (eGFR) was found in the telbivudine-treated group (p < 0.001). In patients with initial eGFR >100 ml/min (n = 34), the median overall survival was significantly longer in the telbivudine-treated group (12.1 vs. 4.9 months; p = 0.042). Preemptive use of telbivudine significantly prevented eGFR deterioration caused by cisplatin-based chemotherapy in HBV-related advanced HCC. In patients with initially sufficient eGFR level, telbivudine treatment was associated with a longer overall survival.

  15. Use of influenza antiviral agents by ambulatory care clinicians during the 2012-2013 influenza season.

    PubMed

    Havers, Fiona; Thaker, Swathi; Clippard, Jessie R; Jackson, Michael; McLean, Huong Q; Gaglani, Manjusha; Monto, Arnold S; Zimmerman, Richard K; Jackson, Lisa; Petrie, Josh G; Nowalk, Mary Patricia; Moehling, Krissy K; Flannery, Brendan; Thompson, Mark G; Fry, Alicia M

    2014-09-15

    Early antiviral treatment (≤2 days since illness onset) of influenza reduces the probability of influenza-associated complications. Early empiric antiviral treatment is recommended for those with suspected influenza at higher risk for influenza complications regardless of their illness severity. We describe antiviral receipt among outpatients with acute respiratory illness (ARI) and antibiotic receipt among patients with influenza. We analyzed data from 5 sites in the US Influenza Vaccine Effectiveness Network Study during the 2012-2013 influenza season. Subjects were outpatients aged ≥6 months with ARI defined by cough of ≤7 days' duration; all were tested for influenza by polymerase chain reaction (PCR). Medical history and prescription information were collected by medical and pharmacy records. Four sites collected prescribing data on 3 common antibiotics (amoxicillin-clavulanate, amoxicillin, and azithromycin). Of 6766 enrolled ARI patients, 509 (7.5%) received an antiviral prescription. Overall, 2366 (35%) had PCR-confirmed influenza; 355 (15%) of those received an antiviral prescription. Among 1021 ARI patients at high risk for influenza complications (eg, aged <2 years or ≥65 years or with ≥1 chronic medical condition) presenting to care ≤2 days from symptom onset, 195 (19%) were prescribed an antiviral medication. Among participants with PCR-confirmed influenza and antibiotic data, 540 of 1825 (30%) were prescribed 1 of 3 antibiotics; 297 of 1825 (16%) were prescribed antiviral medications. Antiviral treatment was prescribed infrequently among outpatients with influenza for whom therapy would be most beneficial; in contrast, antibiotic prescribing was more frequent. Continued efforts to educate clinicians on appropriate antibiotic and antiviral use are essential to improve healthcare quality. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee

  16. Interferon-free therapy of chronic hepatitis C with direct-acting antivirals does not change the short-term risk for de novo hepatocellular carcinoma in patients with liver cirrhosis.

    PubMed

    Mettke, F; Schlevogt, B; Deterding, K; Wranke, A; Smith, A; Port, K; Manns, M P; Vogel, A; Cornberg, M; Wedemeyer, H

    2018-02-01

    Hepatitis C virus (HCV) clearance with IFN-based therapies reduces the incidence of hepatocellular carcinoma (HCC). There has been some debate if IFN-free therapy with direct-acting antivirals alters the risk for HCC. To investigate the HCC incidence in cirrhotic HCV patients who cleared HCV with direct-acting antivirals vs untreated controls. We prospectively monitored 373 patients with chronic hepatitis C who received IFN-free therapies with direct-acting antiviral after January 2014. A retrospective control cohort of untreated cirrhotic patients was recruited out of 3715 HCV patients who were followed at our centre between 2007 and 2013, with similar HCC screening protocols. 158 direct-acting antiviral-treated and 184 control patients with liver cirrhosis were included in this analysis. The groups did not differ in gender and genotype distribution, severity of liver disease and prevalence of diabetes mellitus. Patients were followed up for a median of 440 (range 91-908) and 592 (range 90-1000) days. HCCs developed in 6 and 14 patients during follow-up, resulting in an incidence of 2.90 vs 4.48 HCCs per 100 person-years. In the direct-acting antiviral-treated group, there was no new case of HCC later than 450 days after treatment initiation. In multivariate analysis, higher MELD-Scores and AFP-levels were independently associated with HCC development. Transplant-free patient survival was similar in both groups. IFN-free direct-acting antiviral therapy of chronic hepatitis C does not alter the short-term risk for HCC in patients with liver cirrhosis. A reduced HCC incidence may become evident after more than 1.5 years of follow-up. © 2017 John Wiley & Sons Ltd.

  17. Antiviral therapy during primary simian immunodeficiency virus infection fails to prevent acute loss of CD4+ T cells in gut mucosa but enhances their rapid restoration through central memory T cells.

    PubMed

    Verhoeven, David; Sankaran, Sumathi; Silvey, Melanie; Dandekar, Satya

    2008-04-01

    Gut-associated lymphoid tissue (GALT) is an early target of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and a site for severe CD4+ T-cell depletion. Although antiretroviral therapy (ART) is effective in suppressing HIV replication and restoring CD4+ T cells in peripheral blood, restoration in GALT is delayed. The role of restored CD4+ T-cell help in GALT during ART and its impact on antiviral CD8+ T-cell responses have not been investigated. Using the SIV model, we investigated gut CD4+ T-cell restoration in infected macaques, initiating ART during either the primary stage (1 week postinfection), prior to acute CD4+ cell loss (PSI), or during the chronic stage at 10 weeks postinfection (CSI). ART led to viral suppression in GALT and peripheral blood mononuclear cells of PSI and CSI animals at comparable levels. CSI animals had incomplete CD4+ T-cell restoration in GALT. In PSI animals, ART did not prevent acute CD4+ T-cell loss by 2 weeks postinfection in GALT but supported rapid and complete CD4+ T-cell restoration thereafter. This correlated with an accumulation of central memory CD4+ T cells and better suppression of inflammation. Restoration of CD4+ T cells in GALT correlated with qualitative changes in SIV gag-specific CD8+ T-cell responses, with a dominance of interleukin-2-producing responses in PSI animals, while both CSI macaques and untreated SIV-infected controls were dominated by gamma interferon responses. Thus, central memory CD4+ T-cell levels and qualitative antiviral CD8+ T-cell responses, independent of viral suppression, were the immune correlates of gut mucosal immune restoration during ART.

  18. A New Age-Structured Multiscale Model of the Hepatitis C Virus Life-Cycle During Infection and Therapy With Direct-Acting Antiviral Agents

    SciTech Connect

    Quintela, Barbara de M.; Conway, Jessica M.; Hyman, James M.

    Here, the dynamics of hepatitis C virus (HCV) RNA during translation and replication within infected cells were added to a previous age-structured multiscale mathematical model of HCV infection and treatment. The model allows the study of the dynamics of HCV RNA inside infected cells as well as the release of virus from infected cells and the dynamics of subsequent new cell infections. The model was used to fit in vitro data and estimate parameters characterizing HCV replication. This is the first model to our knowledge to consider both positive and negative strands of HCV RNA with an age-structured multiscale modelingmore » approach. Using this model we also studied the effects of direct-acting antiviral agents (DAAs) in blocking HCV RNA intracellular replication and the release of new virions and fit the model to in vivo data obtained from HCV-infected subjects under therapy.« less

  19. A New Age-Structured Multiscale Model of the Hepatitis C Virus Life-Cycle During Infection and Therapy With Direct-Acting Antiviral Agents

    DOE PAGES

    Quintela, Barbara de M.; Conway, Jessica M.; Hyman, James M.; ...

    2018-04-04

    Here, the dynamics of hepatitis C virus (HCV) RNA during translation and replication within infected cells were added to a previous age-structured multiscale mathematical model of HCV infection and treatment. The model allows the study of the dynamics of HCV RNA inside infected cells as well as the release of virus from infected cells and the dynamics of subsequent new cell infections. The model was used to fit in vitro data and estimate parameters characterizing HCV replication. This is the first model to our knowledge to consider both positive and negative strands of HCV RNA with an age-structured multiscale modelingmore » approach. Using this model we also studied the effects of direct-acting antiviral agents (DAAs) in blocking HCV RNA intracellular replication and the release of new virions and fit the model to in vivo data obtained from HCV-infected subjects under therapy.« less

  20. Long-term liver stiffness assessment in hepatitis C virus patients undergoing antiviral therapy: Results from a 5-year cohort study.

    PubMed

    Facciorusso, Antonio; Del Prete, Valentina; Turco, Antonio; Buccino, Rosario Vincenzo; Nacchiero, Maurizio Cosimo; Muscatiello, Nicola

    2018-04-01

    Observational studies showed significant liver stiffness regression after sustained virological response, but long-term effects of antiviral therapy are still unknown. The aim of this study was to assess the magnitude of change in stiffness up to 5 years after therapy in hepatitis C patients undergoing antiviral treatment. Data of 153 patients were retrieved. Stiffness was assessed by Fibroscan at baseline, end of treatment, 6 months after treatment, and every year hereafter up to 5 years. Seventy patients were treated with interferon-based regimens and 83 with direct antiviral agents. Baseline cirrhosis was diagnosed in 53 (34.6%) patients. Sustained virological response was achieved in 112 patients, whereas 41 were non-responders. In responders, stiffness decreased from 12.3 kPa (9-17.8) to 6.6 kPa (5.3-7.4) at 5 years. A sharper decline was observed immediately after treatment (-2.5 kPa at the end of treatment and -3.7 kPa at 6 months), while from 1 year onwards, the magnitude of stiffness decrease was progressively lower. In non-responders, stiffness showed a slight decrease at the end of treatment (from 19.2 to 18.1 kPa), then returned to baseline levels at 6 months (19.4 kPa), and finally increased over time up to 23.7 kPa (15-32.5) at 5 years. The proportion of cirrhotic patients decreased by 50% at 6 months and finally fell < 5% at 4 years after treatment. Stiffness declines significantly after achieving response, and the magnitude of decline is greater in the first year after treatment, while it tends to plateau from 1 year onwards. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  1. Sequencing of hepatitis C virus for detection of resistance to direct-acting antiviral therapy: A systematic review.

    PubMed

    Bartlett, Sofia R; Grebely, Jason; Eltahla, Auda A; Reeves, Jacqueline D; Howe, Anita Y M; Miller, Veronica; Ceccherini-Silberstein, Francesca; Bull, Rowena A; Douglas, Mark W; Dore, Gregory J; Harrington, Patrick; Lloyd, Andrew R; Jacka, Brendan; Matthews, Gail V; Wang, Gary P; Pawlotsky, Jean-Michel; Feld, Jordan J; Schinkel, Janke; Garcia, Federico; Lennerstrand, Johan; Applegate, Tanya L

    2017-07-01

    The significance of the clinical impact of direct-acting antiviral (DAA) resistance-associated substitutions (RASs) in hepatitis C virus (HCV) on treatment failure is unclear. No standardized methods or guidelines for detection of DAA RASs in HCV exist. To facilitate further evaluations of the impact of DAA RASs in HCV, we conducted a systematic review of RAS sequencing protocols, compiled a comprehensive public library of sequencing primers, and provided expert guidance on the most appropriate methods to screen and identify RASs. The development of standardized RAS sequencing protocols is complicated due to a high genetic variability and the need for genotype- and subtype-specific protocols for multiple regions. We have identified several limitations of the available methods and have highlighted areas requiring further research and development. The development, validation, and sharing of standardized methods for all genotypes and subtypes should be a priority. ( Hepatology Communications 2017;1:379-390).

  2. Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct-acting antiviral therapy.

    PubMed

    Tamori, A; Abiru, S; Enomoto, H; Kioka, K; Korenaga, M; Tani, J; Enomoto, M; Sugiyama, M; Masaki, T; Kawada, N; Yatsuhashi, H; Nishiguchi, S; Mizokami, M

    2018-05-01

    To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon-free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co-infected patients and 765 patients with resolved HBV infection during and after treatment with direct-acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti-HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)-positive patients with an HBV DNA level <2000 IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti-HBs titres at baseline with those at post-DAA therapy in 123 patients without HBsAg. There was no significant difference in anti-HBs levels between the two points (P = .79). In conclusion, HBV reactivation was rare in HBsAg-negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV-reactivated patients with a baseline HBV DNA level <2000 IU/mL before DAA therapy. © 2017 John Wiley & Sons Ltd.

  3. Attendance at specialist hepatitis clinics and initiation of antiviral treatment among persons chronically infected with hepatitis C: examining the early impact of Scotland's Hepatitis C Action Plan.

    PubMed

    McDonald, S A; Hutchinson, S J; Innes, H A; Allen, S; Bramley, P; Bhattacharyya, D; Carman, W; Dillon, J F; Fox, R; Fraser, A; Goldberg, D J; Kennedy, N; Mills, P R; Morris, J; Stanley, A J; Wilks, D; Hayes, P C

    2014-05-01

    Primary goals of the Hepatitis C Action Plan for Scotland Phase II (May 2008-March 2011) were to increase, among persons chronically infected with the hepatitis C (HCV) virus, attendance at specialist outpatient clinics and initiation on antiviral therapy. We evaluated progress towards these goals by comparing the odds, across time, of (a) first clinic attendance within 12 months of HCV diagnosis (n = 9747) and (b) initiation on antiviral treatment within 12 months of first attendance (n = 5736). Record linkage between the national HCV diagnosis (1996-2009) and HCV clinical (1996-2010) databases and logistic regression analyses were conducted for both outcomes. For outcome (a), 32% and 45% in the respective pre-Phase II (before 1 May 2008) and Phase II periods attended a specialist clinic within 12 months of diagnosis; the odds of attendance within 12 months increased over time (OR = 1.05 per year, 95% CI: 1.04-1.07), but was not significantly greater for persons diagnosed with HCV in the Phase II era, compared with the pre-Phase II era (OR = 1.1, 95% CI: 0.9-1.3), after adjustment for temporal trend. For outcome (b), 13% and 28% were initiated on treatment within 12 months of their first clinic attendance in the pre-Phase II and Phase II periods, respectively. Higher odds of treatment initiation were associated with first clinic attendance in the Phase II (OR = 1.9, 95% CI: 1.5-2.4), compared with the pre-Phase II era. Results were consistent with a positive impact of the Hepatitis C Action Plan on the treatment of chronically infected individuals, but further monitoring is required to confirm a sustained effect. © 2013 John Wiley & Sons Ltd.

  4. Antiviral efficacy and safety of abacavir-containing combination antiretroviral therapy as first-line treatment of HIV-infected children and adolescents: a systematic review protocol

    PubMed Central

    2014-01-01

    Background Abacavir is one of the recommended nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infections among children and adolescents. However, there are concerns that the antiviral efficacy of abacavir might be low when compared to other NRTIs especially among children. There are also concerns that abacavir use may lead to serious adverse events such as hypersensitivity reactions and has potential predisposition to developing cardiovascular diseases. Methods We plan to do a systematic review to evaluate the antiviral efficacy and safety of abacavir-containing combination antiretroviral therapy as first-line treatment of HIV-infected children aged between 3 months and 18 years, compared with other NRTIs. We will search Scopus, Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science databases for eligible studies regardless of language or publication status. We will check the reference lists of included studies, search relevant conference proceedings, email the authors of included studies and also look for unpublished and ongoing trials in prospective clinical trial registries. Two authors will independently screen search outputs, select studies, extract data and assess the risk of bias in included studies. All disagreements will be resolved by discussion and consensus. Where data allow, we will conduct meta-analysis for similar types of participants, study designs, interventions, and outcome measures. If the results are statistically homogeneous, we will use the fixed-effect model; otherwise, we will use the random-effects model and explore the reasons for heterogeneity using subgroup analyses. Heterogeneity will be assessed with the Chi-squared test and quantified with the I-squared statistic. Discussion The findings will be useful to policy makers and programme managers to inform treatment and management of HIV in children and adolescents and to point out research gaps for future research. Trial registration

  5. Antiviral efficacy and safety of abacavir-containing combination antiretroviral therapy as first-line treatment of HIV-infected children and adolescents: a systematic review protocol.

    PubMed

    Adetokunboh, Olatunji O; Schoonees, Anel; Wiysonge, Charles S

    2014-08-12

    Abacavir is one of the recommended nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infections among children and adolescents. However, there are concerns that the antiviral efficacy of abacavir might be low when compared to other NRTIs especially among children. There are also concerns that abacavir use may lead to serious adverse events such as hypersensitivity reactions and has potential predisposition to developing cardiovascular diseases. We plan to do a systematic review to evaluate the antiviral efficacy and safety of abacavir-containing combination antiretroviral therapy as first-line treatment of HIV-infected children aged between 3 months and 18 years, compared with other NRTIs. We will search Scopus, Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science databases for eligible studies regardless of language or publication status. We will check the reference lists of included studies, search relevant conference proceedings, email the authors of included studies and also look for unpublished and ongoing trials in prospective clinical trial registries. Two authors will independently screen search outputs, select studies, extract data and assess the risk of bias in included studies. All disagreements will be resolved by discussion and consensus. Where data allow, we will conduct meta-analysis for similar types of participants, study designs, interventions, and outcome measures. If the results are statistically homogeneous, we will use the fixed-effect model; otherwise, we will use the random-effects model and explore the reasons for heterogeneity using subgroup analyses. Heterogeneity will be assessed with the Chi-squared test and quantified with the I-squared statistic. The findings will be useful to policy makers and programme managers to inform treatment and management of HIV in children and adolescents and to point out research gaps for future research. This review is registered with PROSPERO

  6. Naturally occurring deletions/insertions in HBV core promoter tend to decrease in hepatitis B e antigen-positive chronic hepatitis B patients during antiviral therapy.

    PubMed

    Peng, Yaqin; Liu, Baoming; Hou, Jinlin; Sun, Jian; Hao, Ran; Xiang, Kuanhui; Yan, Ling; Zhang, Jiangbo; Zhuang, Hui; Li, Tong

    2015-01-01

    Mutations in HBV core promoter (CP) are suggested to affect viral replication and disease progression. We investigated CP deletion/insertion mutations (Del/Ins) in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients before and during antiviral treatment. Direct and clone sequencings were used for detection of CP Del/Ins in 12 patients. The dynamic changes of CP Del/Ins were tracked in these cases until week 48 of treatment. The effects of Del/Ins on CP activities and hepatitis B X protein (HBx) were analysed using luciferase assay and sequence comparison, respectively. Furthermore, 292 untreated HBeAg-positive CHB cases were also analysed. Twelve cases with multi-peak PCR direct sequencing electropherograms at baseline were confirmed to have CP Del/Ins by clone sequencing, with detection rates varying from 14.8% to 93.3% of clones analysed. Follow-up studies showed the detection rates of CP Del/Ins in patients decreased from 100% (12/12) at baseline to 16.7% (2/12) at week 48 of treatment (P<0.001), in parallel with a decline in HBV DNA, hepatitis B surface antigen (HBsAg), alanine aminotransferase (ALT) and aspartate transaminase (AST) levels along with an increase in HBeAg loss. Luciferase assay results showed distinct promoter activities among Del/Ins-harbouring CP sequences. Importantly, 71.8% (148/206) of Del/Ins sequences potentially resulted in HBx carboxy-terminal truncations. CP Del/Ins mutations were also found in 27.4% (80/292) of untreated cases. Naturally occurring complex of CP Del/Ins mutants existed in untreated HBeAg-positive CHB patients. These mutations would affect HBV transcription activities and integrity of HBx, which might correlate with disease progression. Their prevalence decreases on antiviral therapy in parallel with the decline in HBV DNA, HBsAg and ALT and AST levels.

  7. Exploring virus release as a bottleneck for the spread of influenza A virus infection in vitro and the implications for antiviral therapy with neuraminidase inhibitors

    PubMed Central

    Kowal, Szymon; Cardenas, Daniel A.; Beauchemin, Catherine A. A.

    2017-01-01

    Mathematical models (MMs) have been used to study the kinetics of influenza A virus infections under antiviral therapy, and to characterize the efficacy of antivirals such as neuraminidase inhibitors (NAIs). NAIs prevent viral neuraminidase from cleaving sialic acid receptors that bind virus progeny to the surface of infected cells, thereby inhibiting their release, suppressing infection spread. When used to study treatment with NAIs, MMs represent viral release implicitly as part of viral replication. Consequently, NAIs in such MMs do not act specifically and exclusively on virus release. We compared a MM with an explicit representation of viral release (i.e., distinct from virus production) to a simple MM without explicit release, and investigated whether parameter estimation and the estimation of NAI efficacy were affected by the use of a simple MM. Since the release rate of influenza A virus is not well-known, a broad range of release rates were considered. If the virus release rate is greater than ∼0.1 h−1, the simple MM provides accurate estimates of infection parameters, but underestimates NAI efficacy, which could lead to underdosing and the emergence of NAI resistance. In contrast, when release is slower than ∼0.1 h−1, the simple MM accurately estimates NAI efficacy, but it can significantly overestimate the infectious lifespan (i.e., the time a cell remains infectious and producing free virus), and it will significantly underestimate the total virus yield and thus the likelihood of resistance emergence. We discuss the properties of, and a possible lower bound for, the influenza A virus release rate. PMID:28837615

  8. Photodynamic therapy of virus-associated precancer and early stages cancer of cervix uteri.

    PubMed

    Trushina, O I; Novikova, E G; Sokolov, V V; Filonenko, E V; Chissov, V I; Vorozhtsov, G N

    2008-12-01

    We have analyzed the results of photodynamic therapy using light-sensitizing agent "Photogem" in 72 patients - 56 women with pre-cancerous lesions of cervix and 16 women with early cervical cancer (group 1); Photosens in 47 patients - 35 women with pre-cancerous lesions (CIN III), 12 women with non-invasive cervical cancer (carcinoma in situ) (group 2); and Alasens in 22 patients - 8 women with virus-associated pre-cancerous lesions (high-grade CIN III), 14 with virus-associated early cervical cancer (carcinoma in situ, cervical cancer 1A1) (group 3). The results were as follows: group 1 - complete regression of CIN III and non-invasive cervical cancer (carcinoma in situ) was achieved in 50 (89.2%) and 11 (68.8%) cases, significant regression was achieved in 2 cases (3.6%) and in 2 cases (12.5%), stabilization was achieved in 2 cases (3.6%) and in 2 cases (12.5%), progression was achieved in 2 cases (3.6%) and in 1 case (6.2%) accordingly. In the group of patients after PDT using Photosens complete regression of CIN III and non-invasive cervical cancer (carcinoma in situ) was achieved in 33 cases (94.2%) and in 10 cases (83.4%) cases, significant regression was achieved in 1 case (2.9%) and in 1 case (8.3%), stabilization was achieved in 1 cases (2.9%) and in 1 cases (8.3%). In the group of women after surgical treatment anti-viral efficacy was assessed. It s necessary to note that not a single relapse was observed. Anti-viral effect was registered in 49 (90.4%) cases The longest HPV-free period that we observed was 5 years. 12 women with CIN III and 4 women with carcinoma in situ became pregnant.

  9. Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8+ T-Cell Antiviral Activity and Correlates with Preservation of the CD4+ T-Cell Compartment

    PubMed Central

    Ghiglione, Yanina; Falivene, Juliana; Socias, María Eugenia; Laufer, Natalia; Coloccini, Romina Soledad; Rodriguez, Ana María; Ruiz, María Julia; Pando, María Ángeles; Giavedoni, Luis David; Cahn, Pedro; Sued, Omar; Salomon, Horacio; Gherardi, María Magdalena

    2013-01-01

    The important role of the CD8+ T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8+ T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8+ T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4+ T-cell set points were observed in PHI subjects with higher HIV-specific CD8+ T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-γ. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1β (MIP-1β). All together, this study underscores the importance of CD8+ T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection. PMID:23616666

  10. Newer influenza antivirals, biotherapeutics and combinations.

    PubMed

    Hayden, Frederick G

    2013-01-01

    This summary provides an overview of investigational antiviral agents for influenza and of future directions for development of influenza therapeutics. While progress in developing clinically useful antiviral agents for influenza has been generally slow, especially with respect to seriously ill and high-risk patients, important clinical studies of intravenous neuraminidase inhibitors, antibodies and drug combinations are currently in progress. The current decade offers the promise of developing small molecular weight inhibitors with novel mechanisms of action, including host-directed therapies, new biotherapeutics and drug combinations, that should provide more effective antiviral therapies and help mitigate the problem of antiviral resistance. Immunomodulatory interventions also offer promise but need to be based on better understanding of influenza pathogenesis, particularly in seriously ill patients. The development of combination interventions, immunomodulators and host-directed therapies presents unique clinical trial design and regulatory hurdles that remain to be addressed. © 2012 Blackwell Publishing Ltd.

  11. Changes in liver stiffness and steatosis among patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response.

    PubMed

    Kobayashi, Natsuko; Iijima, Hiroko; Tada, Toshifumi; Kumada, Takashi; Yoshida, Masahiro; Aoki, Tomoko; Nishimura, Takashi; Nakano, Chikage; Takata, Ryo; Yoh, Kazunori; Ishii, Akio; Takashima, Tomoyuki; Sakai, Yoshiyuki; Aizawa, Nobuhiro; Nishikawa, Hiroki; Ikeda, Naoto; Iwata, Yoshinori; Enomoto, Hirayuki; Hirota, Seiichi; Fujimoto, Jiro; Nishiguchi, Shuhei

    2018-05-01

    Whether direct-acting antiviral (DAA) therapy can reduce liver fibrosis and steatosis in patients with chronic hepatitis C virus (HCV) infection remains unclear. We evaluated sequential changes in liver stiffness and steatosis using transient elastography (TE) and the TE-based controlled attenuation parameter (CAP) in patients with HCV who received DAA therapy. A total of 57 patients with HCV who received DAA therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness as evaluated with TE, steatosis as evaluated with CAP, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), 24 weeks after EOT (SVR24), and 48 weeks after EOT (SVR48). Alanine aminotransferase levels, corresponding to the presence of necroinflammatory activity, significantly decreased overall, with significant differences between baseline and EOT, EOT, and SVR24, and baseline and SVR48. However, alanine aminotransferase levels showed no significant changes between SVR24 and SVR48. Median (interquartile range) liver stiffness values at baseline, EOT, SVR24, and SVR48 were 8.3 (5.0-14.8), 7.4 (4.6-14.7), 5.3 (4.1-11.8), and 5.4 (4.0-13.4) kPa, respectively (baseline vs. EOT, P=0.044; EOT vs. SVR24, P=0.011; and SVR24 vs. SVR48, P=0.054). In patients with fatty liver (CAP≥236 dB/m, n=14), CAP values at baseline and SVR48 were 253 (245-278) and 229 (209-249) dB/m, respectively (P=0.020). Liver stiffness at SVR24 might reflect liver fibrosis in the patients who received DAA therapy and achieved SVR. In addition, liver steatosis reduces in the same cohort with fatty liver.

  12. IL-21 Therapy Controls Immune Activation and Maintains Antiviral CD8+ T Cell Responses in Acute Simian Immunodeficiency Virus Infection.

    PubMed

    Méndez-Lagares, Gema; Lu, Ding; Merriam, David; Baker, Christopher A; Villinger, François; Van Rompay, Koen K A; McCune, Joseph M; Hartigan-O'Connor, Dennis J

    2017-11-01

    Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replicate during acute infection in lymphocytes of the gastrointestinal tract, before disseminating systemically. Localized replication and associated loss of gut-resident CD4 + T cells occur regardless of the portal of entry of the virus (e.g., intravenous vs. rectal). Thus, HIV and SIV are tropic for gut tissue, and their pathogenesis requires the special environment of the intestine. T helper 17 (Th17) cells are important contributors to microbial defense in the gut that are vulnerable to HIV infection and whose loss is associated with translocation of microbial products to the systemic circulation, leading to chronic immune activation and disease progression. Interleukin (IL)-21 promotes differentiation and survival of Th17 cells and stimulates CD8 + T cell function. By promoting Th17 cell survival, IL-21 could limit bacterial translocation and immune activation in the setting of acute or rebounding HIV/SIV disease. In this study, we tested the effect of recombinant IL-21-IgFc treatment, given at the time of infection, on SIV mac251 infection. We found that rIL-21-IgFc decreases immune activation and maintains effective antiviral responses by CD8 + T cells in blood, but this maintenance is not associated with lower viral loads. rIL-21-IgFc treatment also did not generally support Th17 cell populations, but Th17 cells remained strongly and independently associated with control of plasma viremia. For example, the single animal exhibiting greatest control over viremia in our study also manifested the highest levels of IL-21 in plasma, Th17 cell maintenance in blood, and Th17 cells in intestinal tissue. These findings provide rationale for further exploration of IL-21 treatment as a support for host CD8 + T cell responses in HIV cure strategies.

  13. Consideration of Viral Resistance for Optimization of Direct Antiviral Therapy of Hepatitis C Virus Genotype 1-Infected Patients.

    PubMed

    Dietz, Julia; Susser, Simone; Berkowski, Caterina; Perner, Dany; Zeuzem, Stefan; Sarrazin, Christoph

    2015-01-01

    Different highly effective interferon-free treatment options for chronic hepatitis C virus (HCV) infection are currently available. Pre-existence of resistance associated variants (RAVs) to direct antiviral agents (DAAs) reduces sustained virologic response (SVR) rates by 3-53% in hepatitis C virus (HCV) genotype 1 infected patients depending on different predictors and the DAA regimen used. Frequencies of single and combined resistance to NS3, NS5A and NS5B inhibitors and consequences for the applicability of different treatment regimens are unknown. Parallel population based sequencing of HCV NS3, NS5A and NS5B genes in 312 treatment-naïve Caucasian HCV genotype 1 infected patients showed the presence of major resistant variants in 20.5% (NS3), 11.9% (NS5A), and 22.1% (NS5B) with important differences for HCV subtypes. In NS3, Q80K was observed in 34.7% and 2.1% of subtype 1a and 1b patients, respectively while other RAVs to second generation protease inhibitors were detected rarely (1.4%). Within NS5A RAVs were observed in 7.1% of subtype 1a and 17.6% in subtype 1b infected patients. RAVs to non-nucleoside NS5B inhibitors were observed in 3.5% and 44.4% of subtype 1a and 1b patients, respectively. Considering all three DAA targets all subtype 1a and 98.6% of subtype 1b infected patients were wildtype for at least one interferon free DAA regimen currently available. In conclusion, baseline resistance testing allows the selection of at least one RAVs-free treatment option for nearly all patients enabling a potentially cost- and efficacy-optimized treatment of chronic hepatitis C.

  14. A cost-effectiveness model to personalize antiviral therapy in naive patients with genotype 1 chronic hepatitis C.

    PubMed

    Iannazzo, Sergio; Colombatto, Piero; Ricco, Gabriele; Oliveri, Filippo; Bonino, Ferruccio; Brunetto, Maurizia R

    2015-03-01

    Rapid virologic response is the best predictor of sustained virologic response with dual therapy in genotype-1 chronic hepatitis C, and its evaluation was proposed to tailor triple therapy in F0-F2 patients. Bio-mathematical modelling of viral dynamics during dual therapy has potentially higher accuracy than rapid virologic in the identification of patients who will eventually achieve sustained response. Study's objective was the cost-effectiveness analysis of a personalized therapy in naïve F0-F2 patients with chronic hepatitis C based on a bio-mathematical model (model-guided strategy) rather than on rapid virologic response (guideline-guided strategy). A deterministic bio-mathematical model of the infected cell dynamics was validated in a cohort of 135 patients treated with dual therapy. A decision-analytic economic model was then developed to compare model-guided and guideline-guided strategies in the Italian setting. The outcomes of the cost-effectiveness analysis with model-guided and guideline-guided strategy were 19.1-19.4 and 18.9-19.3 quality-adjusted-life-years. Total per-patient lifetime costs were €25,200-€26,000 with model-guided strategy and €28,800-€29,900 with guideline-guided strategy. When comparing model-guided with guideline-guided strategy the former resulted more effective and less costly. The adoption of the bio-mathematical predictive criterion has the potential to improve the cost-effectiveness of a personalized therapy for chronic hepatitis C, reserving triple therapy for those patients who really need it. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  15. Direct-acting antiviral-based triple therapy on alpha-fetoprotein level in chronic hepatitis C patients

    PubMed Central

    Takayama, Koji; Furusyo, Norihiro; Ogawa, Eiichi; Ikezaki, Hiroaki; Shimizu, Motohiro; Murata, Masayuki; Hayashi, Jun

    2015-01-01

    AIM: To investigate the impact of telaprevir-based triple therapy on the serum alpha-fetoprotein (AFP) level of chronic hepatitis C patients. METHODS: A total of 210 patients with chronic hepatitis C genotype 1 of high viral load (baseline serum hepatitis C virus RNA > 5.0 log10 IU/mL) were divided into two groups by type of treatment: triple therapy with telaprevir, pegylated-interferon-α (PEG-IFNα), and ribavirin (RBV) for 24 wk (n = 88), or dual therapy with PEG-IFNα and RBV for 48 wk (n = 122). The relationship between virological response and the change in the serum AFP level from baseline to 24 wk after the end of treatment was examined. RESULTS: No significant difference in mean baseline AFP level was found between the triple and dual therapy groups (8.8 ng/mL vs 7.8 ng/mL). Triple therapy produced significant declines in the AFP level in sustained virological response (SVR) and non-SVR patients (7.8 ng/mL at baseline to 3.5 ng/mL at 24 wk after the end of treatment, P < 0.001 and 14.3 ng/mL to 9.5 ng/mL, P = 0.004, respectively). In contrast, dual therapy resulted in a significant decline in AFP level only in SVR patients (4.7 ng/mL to 2.8 ng/mL, P < 0.001), but not in non-SVR patients (10.2 ng/mL to 10.1 ng/mL). Among patients with a high-baseline AFP level (≥ 10 ng/mL), the decline in the AFP level was significantly higher in the triple therapy than in the dual therapy group (15.9 ng/mL vs 1.6 ng/mL, P = 0.037). CONCLUSION: Regardless of virological response, telaprevir-based triple therapy reduced the serum AFP level. PMID:25914481

  16. Direct-acting antiviral-based triple therapy on alpha-fetoprotein level in chronic hepatitis C patients.

    PubMed

    Takayama, Koji; Furusyo, Norihiro; Ogawa, Eiichi; Ikezaki, Hiroaki; Shimizu, Motohiro; Murata, Masayuki; Hayashi, Jun

    2015-04-21

    To investigate the impact of telaprevir-based triple therapy on the serum alpha-fetoprotein (AFP) level of chronic hepatitis C patients. A total of 210 patients with chronic hepatitis C genotype 1 of high viral load (baseline serum hepatitis C virus RNA > 5.0 log10 IU/mL) were divided into two groups by type of treatment: triple therapy with telaprevir, pegylated-interferon-α (PEG-IFNα), and ribavirin (RBV) for 24 wk (n = 88), or dual therapy with PEG-IFNα and RBV for 48 wk (n = 122). The relationship between virological response and the change in the serum AFP level from baseline to 24 wk after the end of treatment was examined. No significant difference in mean baseline AFP level was found between the triple and dual therapy groups (8.8 ng/mL vs 7.8 ng/mL). Triple therapy produced significant declines in the AFP level in sustained virological response (SVR) and non-SVR patients (7.8 ng/mL at baseline to 3.5 ng/mL at 24 wk after the end of treatment, P < 0.001 and 14.3 ng/mL to 9.5 ng/mL, P = 0.004, respectively). In contrast, dual therapy resulted in a significant decline in AFP level only in SVR patients (4.7 ng/mL to 2.8 ng/mL, P < 0.001), but not in non-SVR patients (10.2 ng/mL to 10.1 ng/mL). Among patients with a high-baseline AFP level (≥ 10 ng/mL), the decline in the AFP level was significantly higher in the triple therapy than in the dual therapy group (15.9 ng/mL vs 1.6 ng/mL, P = 0.037). Regardless of virological response, telaprevir-based triple therapy reduced the serum AFP level.

  17. Effectiveness of direct-acting antiviral therapy for hepatitis C in difficult-to-treat patients in a safety-net health system: a retrospective cohort study.

    PubMed

    Yek, Christina; de la Flor, Carolina; Marshall, John; Zoellner, Cindy; Thompson, Grace; Quirk, Lisa; Mayorga, Christian; Turner, Barbara J; Singal, Amit G; Jain, Mamta K

    2017-11-20

    Direct-acting antivirals (DAAs) have revolutionized chronic hepatitis C (HCV) treatment, but real-world effectiveness among vulnerable populations, including uninsured patients, is lacking. This study was conducted to characterize the effectiveness of DAAs in a socioeconomically disadvantaged and underinsured patient cohort. This retrospective observational study included all patients undergoing HCV treatment with DAA-based therapy between April 2014 and June 2016 at a large urban safety-net health system (Parkland Health and Hospital System, Dallas, TX, USA). The primary outcome was sustained virologic response (SVR), with secondary outcomes including treatment discontinuation, treatment relapse, and loss to follow-up. DAA-based therapy was initiated in 512 patients. The cohort was socioeconomically disadvantaged (56% uninsured and 13% Medicaid), with high historic rates of alcohol (41%) and substance (50%) use, and mental health disorders (38%). SVR was achieved in 90% of patients (n = 459); 26 patients (5%) were lost to follow-up. SVR was significantly lower in patients with decompensated cirrhosis (82% SVR; OR 0.37, 95% CI 0.16-0.85) but did not differ by insurance status (P = 0.98) or alcohol/substance use (P = 0.34). Reasons for treatment failure included loss to follow-up (n = 26, 5%), viral relapse (n = 16, 3%), non-treatment-related death (n = 7, 1%), and treatment discontinuation (n = 4, 1%). Of patients with viral relapse, 6 reported non-compliance and have not been retreated, 5 have been retreated and achieved SVR, 4 have undergone resistance testing but not yet initiated retreatment, and 1 was lost to follow-up. Effective outcomes with DAA-based therapy can be achieved in difficult-to-treat underinsured populations followed in resource-constrained safety-net health systems.

  18. Antiviral Natural Products and Herbal Medicines

    PubMed Central

    Lin, Liang-Tzung; Hsu, Wen-Chan; Lin, Chun-Ching

    2014-01-01

    Viral infections play an important role in human diseases, and recent outbreaks in the advent of globalization and ease of travel have underscored their prevention as a critical issue in safeguarding public health. Despite the progress made in immunization and drug development, many viruses lack preventive vaccines and efficient antiviral therapies, which are often beset by the generation of viral escape mutants. Thus, identifying novel antiviral drugs is of critical importance and natural products are an excellent source for such discoveries. In this mini-review, we summarize the antiviral effects reported for several natural products and herbal medicines. PMID:24872930

  19. Nanoparticulate delivery systems for antiviral drugs.

    PubMed

    Lembo, David; Cavalli, Roberta

    2010-01-01

    Nanomedicine opens new therapeutic avenues for attacking viral diseases and for improving treatment success rates. Nanoparticulate-based systems might change the release kinetics of antivirals, increase their bioavailability, improve their efficacy, restrict adverse drug side effects and reduce treatment costs. Moreover, they could permit the delivery of antiviral drugs to specific target sites and viral reservoirs in the body. These features are particularly relevant in viral diseases where high drug doses are needed, drugs are expensive and the success of a therapy is associated with a patient's adherence to the administration protocol. This review presents the current status in the emerging area of nanoparticulate delivery systems in antiviral therapy, providing their definition and description, and highlighting some peculiar features. The paper closes with a discussion on the future challenges that must be addressed before the potential of nanotechnology can be translated into safe and effective antiviral formulations for clinical use.

  20. Radiation therapy in early-stage invasive breast cancer.

    PubMed

    Lin, Ray; Tripuraneni, Prabhakar

    2011-06-01

    The treatment of breast cancer involves a multi-disciplinary approach with radiation therapy playing a key role. Breast-conserving surgery has been an option for women with early-stage breast cancer for over two decades now. Multiple randomized trials now have demonstrated the efficacy of breast-conserving surgery followed by radiation therapy. With the advancements in breast imaging and the successful campaign for early detection of breast cancer, more women today are found to have early-stage small breast cancers. Patient factors (breast size, tumor location, history of prior radiation therapy, preexisting conditions such as collagen vascular disease, age, having prosthetically augmented breasts), pathological factors (margin status, tumor size, presence of extensive intraductal component requiring multiple surgical excisions), as well as patient preference are all taken into consideration prior to surgical management of breast cancer. Whole-breast fractionated radiation therapy between 5 and 7 weeks is considered as the standard of care treatment following breast-conserving surgery. However, new radiation treatment strategies have been developed in recent years to provide alternatives to the conventional 5-7 week whole-breast radiation therapy for some patients. Accelerated partial breast radiation therapy (APBI) was introduced because the frequency of breast recurrences outside of the surgical cavity has been shown to be low. This technique allows treatments to be delivered quicker (usually 1 week, twice daily) to a limited volume. Often times, this treatment involves the use of a brachytherapy applicator to be placed into the surgical cavity following breast-conserving surgery. Accelerated hypofractionated whole-breast irradiation may be another faster way to deliver radiation therapy following breast-conserving surgery. This journal article reviews the role of radiation therapy in women with early-stage breast cancer addressing patient selection in breast

  1. Prognostic factors in patients with hepatitis B virus-related hepatocellular carcinoma undergoing nucleoside analog antiviral therapy

    PubMed Central

    NISHIKAWA, HIROKI; NISHIJIMA, NORIHIRO; ARIMOTO, AKIRA; INUZUKA, TADASHI; KITA, RYUICHI; KIMURA, TORU; OSAKI, YUKIO

    2013-01-01

    In the present era of entecavir (ETV) use for chronic hepatitis B (CHB), the prognostic factors in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unclear. The aims of the present study were to investigate the prognostic factors in patients with HBV-related HCC treated with ETV who underwent curative therapy. A total of 74 HBV-related HCC patients treated with ETV who underwent curative therapy were analyzed. Predictive factors associated with overall survival (OS) and recurrence-free survival (RFS) were examined using univariate and multivariate analysis. Our study population included 49 males and 25 females with a median age of 62 years. The median observation period was 3.4 years (range, 0.2–11.5 years). The 1-, 3- and 5-year cumulative OS rates were 100, 89.8 and 89.8%, respectively. The corresponding RFS rates were 82.8, 52.1 and 25.6%, respectively. In this study, 73 patients (98.6%) achieved an HBV DNA level of <400 copies/ml during the follow-up period. No viral breakthrough hepatitis, as defined by 1 log increase from nadir, was observed during ETV therapy. According to multivariate analysis, only hepatitis B e antigen (HBeAg) positivity was significantly associated with OS [hazard ratio (HR), 0.058; 95% confidence interval (CI), 0.005–0.645; P=0.020)], whereas HCC stage (HR, 0.359; 95% CI, 0.150–0.859; P=0.021), HBeAg positivity (HR, 0.202; 95% CI, 0.088–0.463; P<0.001) and γ-glutamyl transpeptidase ≥50 IU/l (HR, 0.340; 95% CI, 0.152–0.760; P=0.009) were significant predictive factors linked to RFS. In conclusion, HBeAg positivity was significantly associated with OS and RFS in HBV-related HCC patients treated with ETV who underwent curative therapy. In such patients, close observation is required, even after curative therapy for HCC. PMID:24179497

  2. The RNA template channel of the RNA-dependent RNA polymerase as a target for development of antiviral therapy of multiple genera within a virus family.

    PubMed

    van der Linden, Lonneke; Vives-Adrián, Laia; Selisko, Barbara; Ferrer-Orta, Cristina; Liu, Xinran; Lanke, Kjerstin; Ulferts, Rachel; De Palma, Armando M; Tanchis, Federica; Goris, Nesya; Lefebvre, David; De Clercq, Kris; Leyssen, Pieter; Lacroix, Céline; Pürstinger, Gerhard; Coutard, Bruno; Canard, Bruno; Boehr, David D; Arnold, Jamie J; Cameron, Craig E; Verdaguer, Nuria; Neyts, Johan; van Kuppeveld, Frank J M

    2015-03-01

    The genus Enterovirus of the family Picornaviridae contains many important human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and enterovirus 71) for which no antiviral drugs are available. The viral RNA-dependent RNA polymerase is an attractive target for antiviral therapy. Nucleoside-based inhibitors have broad-spectrum activity but often exhibit off-target effects. Most non-nucleoside inhibitors (NNIs) target surface cavities, which are structurally more flexible than the nucleotide-binding pocket, and hence have a more narrow spectrum of activity and are more prone to resistance development. Here, we report a novel NNI, GPC-N114 (2,2'-[(4-chloro-1,2-phenylene)bis(oxy)]bis(5-nitro-benzonitrile)) with broad-spectrum activity against enteroviruses and cardioviruses (another genus in the picornavirus family). Surprisingly, coxsackievirus B3 (CVB3) and poliovirus displayed a high genetic barrier to resistance against GPC-N114. By contrast, EMCV, a cardiovirus, rapidly acquired resistance due to mutations in 3Dpol. In vitro polymerase activity assays showed that GPC-N114 i) inhibited the elongation activity of recombinant CVB3 and EMCV 3Dpol, (ii) had reduced activity against EMCV 3Dpol with the resistance mutations, and (iii) was most efficient in inhibiting 3Dpol when added before the RNA template-primer duplex. Elucidation of a crystal structure of the inhibitor bound to CVB3 3Dpol confirmed the RNA-binding channel as the target for GPC-N114. Docking studies of the compound into the crystal structures of the compound-resistant EMCV 3Dpol mutants suggested that the resistant phenotype is due to subtle changes that interfere with the binding of GPC-N114 but not of the RNA template-primer. In conclusion, this study presents the first NNI that targets the RNA template channel of the picornavirus polymerase and identifies a new pocket that can be used for the design of broad-spectrum inhibitors. Moreover, this study provides important new insight into the

  3. The RNA Template Channel of the RNA-Dependent RNA Polymerase as a Target for Development of Antiviral Therapy of Multiple Genera within a Virus Family

    PubMed Central

    van der Linden, Lonneke; Vives-Adrián, Laia; Selisko, Barbara; Ferrer-Orta, Cristina; Liu, Xinran; Lanke, Kjerstin; Ulferts, Rachel; De Palma, Armando M.; Tanchis, Federica; Goris, Nesya; Lefebvre, David; De Clercq, Kris; Leyssen, Pieter; Lacroix, Céline; Pürstinger, Gerhard; Coutard, Bruno; Canard, Bruno; Boehr, David D.; Arnold, Jamie J.; Cameron, Craig E.; Verdaguer, Nuria

    2015-01-01

    The genus Enterovirus of the family Picornaviridae contains many important human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and enterovirus 71) for which no antiviral drugs are available. The viral RNA-dependent RNA polymerase is an attractive target for antiviral therapy. Nucleoside-based inhibitors have broad-spectrum activity but often exhibit off-target effects. Most non-nucleoside inhibitors (NNIs) target surface cavities, which are structurally more flexible than the nucleotide-binding pocket, and hence have a more narrow spectrum of activity and are more prone to resistance development. Here, we report a novel NNI, GPC-N114 (2,2'-[(4-chloro-1,2-phenylene)bis(oxy)]bis(5-nitro-benzonitrile)) with broad-spectrum activity against enteroviruses and cardioviruses (another genus in the picornavirus family). Surprisingly, coxsackievirus B3 (CVB3) and poliovirus displayed a high genetic barrier to resistance against GPC-N114. By contrast, EMCV, a cardiovirus, rapidly acquired resistance due to mutations in 3Dpol. In vitro polymerase activity assays showed that GPC-N114 i) inhibited the elongation activity of recombinant CVB3 and EMCV 3Dpol, (ii) had reduced activity against EMCV 3Dpol with the resistance mutations, and (iii) was most efficient in inhibiting 3Dpol when added before the RNA template-primer duplex. Elucidation of a crystal structure of the inhibitor bound to CVB3 3Dpol confirmed the RNA-binding channel as the target for GPC-N114. Docking studies of the compound into the crystal structures of the compound-resistant EMCV 3Dpol mutants suggested that the resistant phenotype is due to subtle changes that interfere with the binding of GPC-N114 but not of the RNA template-primer. In conclusion, this study presents the first NNI that targets the RNA template channel of the picornavirus polymerase and identifies a new pocket that can be used for the design of broad-spectrum inhibitors. Moreover, this study provides important new insight into the

  4. Impact of Direct Acting Antiviral Therapy for Treatment of Hepatitis C Genotypes 1, 3 and 4: A Real Life Experience from India.

    PubMed

    Mehta, Varun; Mahajan, Ramit; Midha, Vandana; Narang, Vikram; Kaur, Kirandeep; Singh, Arshdeep; Malhotra, Anand; Parvez, Aslam; Sood, Ajit

    2018-03-01

    To assess impact of Direct Acting Antiviral (DAA) therapies for treatment of Hepatitis C Virus (HCV) genotypes 1, 3 and 4 in a real-world cohort from India. Adults with chronic HCV infection treated with Sofosbuvir (SOF) and Ledipasvir (LDV) (genotypes 1 and 4) or SOF and Daclatasvir (DCV) (genotype 3), with or without Ribavirin (RBV) between December 2015 and December 2016 were included. The primary endpoint was Sustained Virological Response at Post-treatment Week 12 (SVR12). Of the 648 patients, 181 received SOF/LDV (65 with RBV) and 467 received SOF/DCV (135 with RBV). Most patients were males (65.4%), aged 41-60 years (49.4%) and treatment-naïve (92.6%). Genotype 3 (72.1%) was most common, followed by genotypes 1 (22.4%) and 4 (5.6%). Forty two percent patients ( n  = 271) had cirrhosis (112 patients were decompensated). SVR12 (modified intention-to-treat) was achieved by 98.1% of patients (512/522) (100% in genotypes 1 and 4, and 97.3% (362/372) in genotype 3). On intention to treat analysis, SVR12 was 88.1% (512/581) [genotype 1-96.8% (121/125), genotype 3-85.2%, genotype 4-93.5% (29/31)]. Seventy patients had treatment failure (non response in 6, virological breakthrough in 2, 10 patients relapsed, 2 died and 50 were lost to follow up). High SVR was observed regardless of HCV genotype, presence of cirrhosis or past history of treatment. No major adverse events warranting discontinuation of treatment were noted. DAA therapy for HCV genotypes 1, 3 and 4 achieves high SVR rates in all patients, including those with cirrhosis and previous non-responders.

  5. Risk of pure red cell aplasia in patients with hepatitis C receiving antiviral therapy and an erythropoiesis-stimulating agent.

    PubMed

    Rossert, Jerome; Yue, Susan; Smirnakis, Karen; Mytych, Daniel T; Johnson, Larry; Kouchakji, Elias; Casadevall, Nicole

    2014-02-01

    Antibody-mediated pure red cell aplasia (PRCA) has been primarily observed in patients with chronic kidney disease treated with an erythropoiesis-stimulating agent (ESA); only a few anecdotal cases have been reported in other patient populations. We searched the Amgen Global Safety Adverse Event Database and identified 14 patients with hepatitis C who developed severe anemia, anti-erythropoietin antibodies, and bone marrow biopsy-proven PRCA, while receiving interferon therapy (with or without ribavirin) and an ESA. During the follow-up period and after ESA treatment stopped, 11 patients no longer required transfusions and 3 did. Analysis of antibody isotypes showed that, contrary to reports of patients with chronic kidney disease, immunoglobulin G1 was the predominant isotype rather than immunoglobulin G4 (immunoglobulin G4 was detected in only 1 of 6 patients). Epitope mapping showed the anti-erythropoietin antibodies bound domains required for receptor binding. Therefore, the potential benefits of ESA therapy must be weighed against the risk for PRCA in patients with hepatitis C who are receiving treatment with interferon and ribavirin. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  6. Week 4 response predicts sustained virological response to all-oral direct-acting antiviral-based therapy in cirrhotic patients with hepatitis C virus genotype 3 infection.

    PubMed

    Pineda, J A; Morano-Amado, L E; Granados, R; Macías, J; Téllez, F; García-Deltoro, M; Ríos, M J; Collado, A; Delgado-Fernández, M; Suárez-Santamaría, M; Serrano, M; Miralles-Álvarez, C; Neukam, K

    2017-06-01

    The aim of this study was to determine the predictive capacity of response at treatment week (TW) 4 for the achievement of sustained virological response 12 weeks after the scheduled end of therapy date (SVR 12 ) to treatment against hepatitis C virus (HCV) genotype 3 (GT3) infection with all-oral direct-acting antiviral (DAA) -based regimens. From a prospective multicohort study, HCV GT3-infected patients who completed a course of currently recommended DAA-based therapy at 33 Spanish hospitals and who had reached the SVR 12 evaluation time-point were selected. TW4 HCV-RNA levels were categorized as target-not-detected (TND), below the lower limit of quantification (LLOQ TD ) and ≥LLOQ. A total of 123 patients were included, 86 (70%) received sofosbuvir/ daclatasvir±ribavirin, 27 (22%) received sofosbuvir/ ledipasvir/ ribavirin and 10 (8.1%) received sofosbuvir/ ribavirin, respectively. In all, 114 (92.7%) of the 123 patients presented SVR 12 in an on-treatment approach, but nine (7.3%) patients relapsed, all of them had presented cirrhosis at baseline. In those who achieved TND, LLOQ TD and ≥LLOQ, SVR 12 was observed in 81/83 (98%; 95% CI 91.5%-99.7%), 24/28 (85.7%; 95% CI 67.3%-96%) and 9/12 (75%; 95% CI 42.8%-94.5%), respectively; p (linear association) 0.001. Corresponding numbers for subjects with cirrhosis were: 52/54 (96.3%; 95% CI 87.3%-95.5%), 14/18 (77.8%; 95% CI 52.4%-93.6%) and 7/10 (70%; 95% CI 34.8%-93.3%); p 0.004. TW4-response indicates the probability of achieving SVR 12 to currently used DAA-based therapy in HCV genotype 3-infected individuals with cirrhosis. This finding may be useful to tailor treatment strategy in this setting. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  7. Immunological dynamics associated with rapid virological response during the early phase of type I interferon therapy in patients with chronic hepatitis C.

    PubMed

    Lee, Jae-Won; Kim, Won; Kwon, Eun-Kyung; Kim, Yuri; Shin, Hyun Mu; Kim, Dong-Hyun; Min, Chan-Ki; Choi, Ji-Yeob; Lee, Won-Woo; Choi, Myung-Sik; Kim, Byeong Gwan; Cho, Nam-Hyuk

    2017-01-01

    Type I interferons (IFNs) play an important role in antiviral immunity as well as immunopathogenesis of diverse chronic viral infections. However, the precise mechanisms regulating the multifaceted effects of type I IFNs on the immune system and pathological inflammation still remain unclear. In order to assess the immunological dynamics associated with rapid viral clearance in chronic hepatitis C patients during the acute phase of type I IFN therapy, we analyzed multiple parameters of virological and immunological responses in a cohort of 59 Korean hepatitis C patients who received pegylated IFN-α and ribavirin (IFN/RBV). Most of the Korean patients had favorable alleles in the IFN-λ loci for responsiveness to IFN/RBV (i.e., C/C in rs12979860, T/T in rs8099917, and TT/TT in rs368234815). Rapid virological response (RVR) was determined mainly by the hepatitis C virus genotype. Among the cytokines analyzed, higher plasma levels of IL-17A and FGF were observed in non-RVR patients infected with viral genotype 1 and IP-10 was consistently elevated in RVR group infected with genotype 2 during the early phase of antiviral therapy. In addition, these three cytokines were correlated each other, suggesting a functional linkage of the cytokines in antiviral responses during IFN/RBV therapy. A low baseline frequencies of regulatory T cells and γδ T cells, but high level of group 2 innate lymphoid cells, in peripheral bloods were also significantly associated with the RVR group, implicating a potential role of the cellular immunity during the early phase of IFN/RBV therapy. Therefore, the immunological programs established by chronic hepatitis C and rapid disruption of the delicate balance by exogenous type I IFN might be associated with the subsequent virological outcomes in chronic hepatitis C patients.

  8. Immunological dynamics associated with rapid virological response during the early phase of type I interferon therapy in patients with chronic hepatitis C

    PubMed Central

    Lee, Jae-Won; Kim, Won; Kwon, Eun-Kyung; Kim, Yuri; Shin, Hyun Mu; Kim, Dong-Hyun; Min, Chan-Ki; Choi, Ji-Yeob; Lee, Won-Woo; Choi, Myung-Sik; Kim, Byeong Gwan

    2017-01-01

    Type I interferons (IFNs) play an important role in antiviral immunity as well as immunopathogenesis of diverse chronic viral infections. However, the precise mechanisms regulating the multifaceted effects of type I IFNs on the immune system and pathological inflammation still remain unclear. In order to assess the immunological dynamics associated with rapid viral clearance in chronic hepatitis C patients during the acute phase of type I IFN therapy, we analyzed multiple parameters of virological and immunological responses in a cohort of 59 Korean hepatitis C patients who received pegylated IFN-α and ribavirin (IFN/RBV). Most of the Korean patients had favorable alleles in the IFN-λ loci for responsiveness to IFN/RBV (i.e., C/C in rs12979860, T/T in rs8099917, and TT/TT in rs368234815). Rapid virological response (RVR) was determined mainly by the hepatitis C virus genotype. Among the cytokines analyzed, higher plasma levels of IL-17A and FGF were observed in non-RVR patients infected with viral genotype 1 and IP-10 was consistently elevated in RVR group infected with genotype 2 during the early phase of antiviral therapy. In addition, these three cytokines were correlated each other, suggesting a functional linkage of the cytokines in antiviral responses during IFN/RBV therapy. A low baseline frequencies of regulatory T cells and γδ T cells, but high level of group 2 innate lymphoid cells, in peripheral bloods were also significantly associated with the RVR group, implicating a potential role of the cellular immunity during the early phase of IFN/RBV therapy. Therefore, the immunological programs established by chronic hepatitis C and rapid disruption of the delicate balance by exogenous type I IFN might be associated with the subsequent virological outcomes in chronic hepatitis C patients. PMID:28614389

  9. Immunogenetic studies of the hepatitis C virus infection in an era of pan-genotype antiviral therapies - Effective treatment is coming.

    PubMed

    Ellwanger, Joel Henrique; Kaminski, Valéria de Lima; Valverde-Villegas, Jacqueline María; Simon, Daniel; Lunge, Vagner Ricardo; Chies, José Artur Bogo

    2017-08-12

    What are the factors that influence human hepatitis C virus (HCV) infection, hepatitis status establishment, and disease progression? Firstly, one has to consider the genetic background of the host and HCV genotypes. The immunogenetic host profile will reflect how each infected individual deals with infection. Secondly, there are environmental factors that drive susceptibility or resistance to certain viral strains. These will dictate (I) the susceptibility to infection; (II) whether or not an infected person will promote viral clearance; (III) the immune response and the response profile to therapy; and (IV) whether and how long it would take to the development of HCV-associated diseases, as well as their severity. Looking at this scenario, this review addresses clinical aspects of HCV infection, following by an update of molecular and cellular features of the immune response against the virus. The evasion mechanisms used by HCV are presented, considering the potential role of exosomes in infection. Genetic factors influencing HCV infection and pathogenesis are the main topics of the article. Shortly, HLAs, MBLs, TLRs, ILs, and IFNLs genes have relevant roles in the susceptibility to HCV infection. In addition, ILs, IFNLs, as well as TLRs genes are important modulators of HCV-associated diseases. The viral aspects that influence HCV infection are presented, followed by a discussion about evolutionary aspects of host and HCV interaction. HCV and HIV infections are close related. Thus, we also present a discussion about HIV/HCV co-infection, focusing on cellular and molecular aspects of this interaction. Pharmacogenetics and treatment of HCV infection are the last topics of this review. The understanding of how the host genetics interacts with viral and environmental factors is crucial for the development of new strategies to prevent HCV infection, even in an era of potential development of pan-genotypic antivirals. Copyright © 2017 Elsevier B.V. All rights

  10. High HCV cure rates for people who use drugs treated with direct acting antiviral therapy at an urban primary care clinic.

    PubMed

    Norton, Brianna L; Fleming, Julia; Bachhuber, Marcus A; Steinman, Meredith; DeLuca, Joseph; Cunningham, Chinazo O; Johnson, Nirah; Laraque, Fabienne; Litwin, Alain H

    2017-09-01

    Though direct acting antivirals (DAAs) promise high cure rates, many providers and payers remain concerned about successful treatment for people who use drugs (PWUD), even among those engaged in opioid agonist treatment (OAT). The efficacy of DAAs among PWUD in real-world settings is unclear. We conducted a cohort study of patients initiating HCV treatment between January 2014 and August 2015 (n=89) at a primary care clinic in the Bronx, NY. Onsite HCV treatment with DAAs was performed by an HCV specialist, with support from a care coordinator funded by the NYC Department of Health. We identified four categories of drug use and drug treatment: (1) no active drug use/not receiving OAT (defined as non-PWUD); (2) no active drug use/receiving OAT; (3) active drug use/not receiving OAT; and (4) active drug use/receiving OAT. The primary outcome was SVR at 12 weeks post-treatment. Overall SVR rates were 95% (n=41/43) for non-PWUD and 96% (n=44/46) for patients actively using drugs and/or receiving OAT [p=0.95]. There were no differences in SVR rates by drug use or drug treatment category. Compared to non-PWUD, those with no active drug use/receiving OAT had 100% SVR (n=15/15; p=1.0), those actively using drugs/not receiving OAT had 90% SVR (n=9/10; p=0.47), and those actively using drugs/receiving OAT had 95% SVR (20/21; p=1.0). Regardless of active drug use or OAT, patients who received DAA therapy at an urban primary care clinic achieved high HCV cure rates. We found no clinical evidence to justify restricting access to HCV treatment for patients actively using drugs and/or receiving OAT. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. High HCV cure rates for people who use drugs treated with direct acting antiviral therapy at an urban primary care clinic

    PubMed Central

    Norton, Brianna L.; Fleming, Julia; Bachhuber, Marcus A.; Steinman, Meredith; DeLuca, Joseph; Cunningham, Chinazo O.; Johnson, Nirah; Laraque, Fabienne; Litwin, Alain H.

    2018-01-01

    Background Though direct acting antivirals (DAAs) promise high cure rates, many providers and payers remain concerned about successful treatment for people who use drugs (PWUD), even among those engaged in opioid agonist treatment (OAT). The efficacy of DAAs among PWUD in real-world settings is unclear. Methods We conducted a cohort study of patients initiating HCV treatment between January 2014 and August 2015 (n = 89) at a primary care clinic in the Bronx, NY. Onsite HCV treatment with DAAs was performed by an HCV specialist, with support from a care coordinator funded by the NYC Department of Health. We identified four categories of drug use and drug treatment: (1) no active drug use/not receiving OAT (defined as non-PWUD); (2) no active drug use/receiving OAT; (3) active drug use/not receiving OAT; and (4) active drug use/receiving OAT. The primary outcome was SVR at 12 weeks post-treatment. Results Overall SVR rates were 95% (n = 41/43) for non-PWUD and 96% (n = 44/46) for patients actively using drugs and/or receiving OAT [p = 0.95]. There were no differences in SVR rates by drug use or drug treatment category. Compared to non-PWUD, those with no active drug use/receiving OAT had 100% SVR (n = 15/15; p = 1.0), those actively using drugs/not receiving OAT had 90% SVR (n = 9/10; p = 0.47), and those actively using drugs/receiving OAT had 95% SVR (20/21; p = 1.0). Conclusion Regardless of active drug use or OAT, patients who received DAA therapy at an urban primary care clinic achieved high HCV cure rates. We found no clinical evidence to justify restricting access to HCV treatment for patients actively using drugs and/or receiving OAT. PMID:28811158

  12. Prevalence of Congenital CMV Infection and Antiviral Therapy in Very-Low-Birth-Weight Infants: Observations of the German Neonatal Network.

    PubMed

    Humberg, Alexander; Leienbach, Viola; Fortmann, Mats I; Rausch, Tanja K; Buxmann, Horst; Müller, Andreas; Herting, Egbert; Härtel, Christoph; Göpel, Wolfgang

    2018-04-18

    To determine the prevalence of congenital CMV infection (cCMV) in very-low-birth-weight infants (VLBWI) and to evaluate epidemiological characteristics of VLBWI with antiviral therapy (AT). CMV-specific PCR in umbilical cord tissue was performed (n=3330). Univariate analyses and logistic regression models were used to identify associations with outcome. 22/3330 VLBWI received AT (0.66%). 4 of these (0.12%) were PCR positive, with 2 VLBWI showing pathological screening for hearing loss. VLBWI with AT and negative PCR had significantly reduced mean birth weight (BW) and higher rates of small-for-gestational-age (SGA). Clinical sepsis, bronchopulmonary dysplasia (BPD), use of reserve antibiotics (RA) and treatment for retinopathy of prematurity were significantly increased. We further observed a higher need of transfusion of red blood cells (RBC), fresh frozen plasma and platelets. Logistic regression (controlled for gender, gestational age, SGA and BW) showed associations for AT and BPD (OR 3.4 [1.2-10.1], p=0.024), RA (OR 20.4 [4.2-98.9], p≤0.001), transfusions of RBC (OR 11.9 [1.3-105.7], p=0.026) and platelets (OR 8.7 [2.9-26.4], p≤0.001). All VLBWI with positive PCR received AT. We hypothesize from our data by assuming a postnatal aquired CMV infection in VLBWI with AT and negative PCR that VLBWI born SGA have a different risk profile. Further prospective studies concerning postnatal transmission should take VLBWI born SGA into account and should study the impact of infection on short- and long-term complications in this supposed vulnerable group. © Georg Thieme Verlag KG Stuttgart · New York.

  13. Long-Term Follow-Up of Resistance-Associated Substitutions in Hepatitis C Virus in Patients in Which Direct Acting Antiviral-Based Therapy Failed.

    PubMed

    Yoshida, Kanako; Hai, Hoang; Tamori, Akihiro; Teranishi, Yuga; Kozuka, Ritsuzo; Motoyama, Hiroyuki; Kawamura, Etsushi; Hagihara, Atsushi; Uchida-Kobayashi, Sawako; Morikawa, Hiroyasu; Enomoto, Masaru; Murakami, Yoshiki; Kawada, Norifumi

    2017-05-03

    We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.

  14. What is the impact of a country-wide scale-up in antiviral therapy on the characteristics and sustained viral response rates of patients treated for hepatitis C?

    PubMed

    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

    2015-02-01

    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.

  15. Delivering direct acting antiviral therapy for hepatitis C to highly marginalised and current drug injecting populations in a targeted primary health care setting.

    PubMed

    Read, Phillip; Lothian, Rebecca; Chronister, Karen; Gilliver, Rosie; Kearley, John; Dore, Gregory J; van Beek, Ingrid

    2017-09-01

    The Kirketon Road Centre (KRC) is a community-based public health facility in Sydney, Australia, that provides healthcare to people who inject drugs (PWID), including hepatitis C virus (HCV) treatment. From March 2016, the Australian Government has provided access to direct-acting antivirals (DAA) for adults with chronic HCV, without liver disease stage or drug and alcohol use restrictions. The aim of this study was to report DAA treatment outcomes among highly marginalised PWID treated at KRC. All individuals initiating DAA treatment at KRC and due for sustained virological response (SVR12) testing by end 2016 were included. Demographic, drug use behaviour, clinical parameters, adherence support and HCV treatment outcomes, including SVR12 were recorded. Factors associated with SVR12, loss-to-follow-up (LTFU) and delayed SVR12 testing (>SVR16) were assessed by multivariate analysis. SVR12 was assessed by intention-to-treat (ITT) and modified ITT, the latter excluding individuals with an end-of-treatment response (ETR) but no SVR12 assessment, or who postponed their SVR12 date due to treatment interruption. A total of 72 individuals commencing DAAs were included, of whom 67% were male, 30% homeless, and 32% Aboriginal. All had a lifetime history of injecting drug use, with 75% having injected within the last six months, and 44% injecting at least weekly; 25% were also enrolled in opioid substitution therapy. Twenty-five (35%) individuals elected to receive an enhanced adherence-support package. Fifty-nine of 72 (82%) individuals due for SVR12 attended for testing, of whom 59/59 (100%) achieved SVR, providing an ITT SVR of 82%. A further six individuals had undetectable HCV RNA at ETR, but no SVR12 assessment, and one interrupted treatment, providing a mITT SVR of 91%. Homelessness was associated with delayed SVR12 testing (OR 24.9 95%CI 2.9-212.8, p=0.003). There was no association between LTFU and frequency of drug injection, last drug injected, or planned

  16. Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: Results from a Spanish real-world cohort.

    PubMed

    Calleja, Jose Luis; Crespo, Javier; Rincón, Diego; Ruiz-Antorán, Belén; Fernandez, Inmaculada; Perelló, Christie; Gea, Francisco; Lens, Sabela; García-Samaniego, Javier; Sacristán, Begoña; García-Eliz, María; Llerena, Susana; Pascasio, Juan Manuel; Turnes, Juan; Torras, Xavier; Morillas, Rosa Maria; Llaneras, Jordi; Serra, Miguel A; Diago, Moises; Rodriguez, Conrado Fernández; Ampuero, Javier; Jorquera, Francisco; Simon, Miguel A; Arenas, Juan; Navascues, Carmen Alvarez; Bañares, Rafael; Muñoz, Raquel; Albillos, Agustin; Mariño, Zoe

    2017-06-01

    Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of

  17. Newer influenza antivirals, biotherapeutics and combinations

    PubMed Central

    Hayden, Frederick G.

    2012-01-01

    Please cite this paper as: Hayden FG. (2012) Newer Influenza Antivirals, Biotherapeutics and Combinations. Influenza and Other Respiratory Viruses 7(Suppl. 1), 63–75. This summary provides an overview of investigational antiviral agents for influenza and of future directions for development of influenza therapeutics. While progress in developing clinically useful antiviral agents for influenza has been generally slow, especially with respect to seriously ill and high‐risk patients, important clinical studies of intravenous neuraminidase inhibitors, antibodies and drug combinations are currently in progress. The current decade offers the promise of developing small molecular weight inhibitors with novel mechanisms of action, including host‐directed therapies, new biotherapeutics and drug combinations, that should provide more effective antiviral therapies and help mitigate the problem of antiviral resistance. Immunomodulatory interventions also offer promise but need to be based on better understanding of influenza pathogenesis, particularly in seriously ill patients. The development of combination interventions, immunomodulators and host‐directed therapies presents unique clinical trial design and regulatory hurdles that remain to be addressed. PMID:23279899

  18. Could lengthening minocycline therapy better treat early syphilis?

    PubMed

    Shao, Li-Li; Guo, Rui; Shi, Wei-Jie; Liu, Yuan-Jun; Feng, Bin; Han, Long; Liu, Quan-Zhong

    2016-12-01

    Syphilis is a sexually transmitted disease caused by Treponema pallidum. Minocycline, a representative tetracycline derivative, has the greatest antimicrobial activity among all tetracyclines. There are few reports about treating syphilis with minocycline because there is a lack of efficacy data from controlled trials. We compared the rates of serological cure in patients with early syphilis who were treated with minocycline or benzathine penicillin G (BPG).During the study period, a total of 40 syphilis patients received the BPG treatment, which was a single intramuscular dose of 2.4 million units of BPG, and 156 patients were treated with minocycline; 77 patients were placed in the 2-week, standard minocycline therapy group and received 100 mg of minocycline orally, twice daily for 14 days, and 79 patients were placed in the 4-week, lengthened minocycline therapy group and received 100 mg of minocycline orally, twice daily for 28 days. The outcome of interest was the rate of serological cure in these patients.At the end of the 2-year follow-up, the serological cure rate of the 4-week, lengthened minocycline therapy group (87.34%) was higher than that of both the 2-week, standard minocycline therapy group (72.73%) and the BPG treatment group (77.50%). In addition, the curative effect of the 4-week, lengthened minocycline therapy was significantly greater than that of the 2-week, standard minocycline therapy in patients who were aged >40 years; exhibited an initial rapid plasma reagin titer ≥1: 32; or exhibited secondary syphilis (P = 0.000, 0.008, 0.000; <0.05).Minocycline appears to be an effective agent for treating early syphilis, especially when applied as a 4-week, lengthened therapy.

  19. Antiviral T-cell therapy

    PubMed Central

    Leen, Ann M; Heslop, Helen E; Brenner, Malcolm K

    2013-01-01

    Summary Serious viral infections are a common cause of morbidity and mortality after allogeneic stem cell transplantation. They occur in the majority of allograft recipients and are fatal in 17–20%. These severe infections may be prolonged or recurrent and add substantially to the cost, both human and financial, of the procedure. Many features of allogeneic stem cell transplantation contribute to this high rate of viral disease. The cytotoxic and immunosuppressive drugs administered pre-transplant to eliminate the host hematopoietic/immune system and any associated malignancy, the delay in recapitulating immune ontogeny post-transplant, the immunosuppressive drugs given to prevent graft versus host disease (GvHD), and the effects of GvHD itself, all serve to make stem cell transplant recipients vulnerable to disease from endogenous (latent) and exogenous (community) viruses, and to be incapable of controlling them as quickly and effectively as most normal individuals. PMID:24517423

  20. Carrier-Mediated Antiviral Therapy

    DTIC Science & Technology

    1988-01-01

    methyimethacrylate). (x) Adsorption onto 0.2% aluminium hydroxide. (L) Fluid vaccine. The vaccines with nanoparticles as adjuvants were tested by...such treatment regimens, the doses of the interferons needed to obtain efficacy can result in toxic side effects. For all these reasons, methods of...adjuvants can be used in human vaccines. Besides the classic aluminum adjuvants. particulate polymeric carriers, the so-called nanoparticles , hold promise for

  1. Endoscopic Therapy of Early Carcinoma of the Oesophagus

    PubMed Central

    Knabe, Mate; May, Andrea; Ell, Christian

    2015-01-01

    Summary Background Oesophageal cancer is a comparatively rare disease in the Western world. Prognosis is highly dependent on the choice of treatment. Early stages can be treated by endoscopic resection, whereas surgery needs to be performed in the case of advanced carcinomas. Technical progress has enabled high-definition endoscopes and technical add-ons which help the endoscopist in finding fine irregularities in the oesophageal mucosa, though interpretation still remains challenging. Methods In this review, we discuss both novel and old diagnostic procedures and their value, as well as the current recommendations for the diagnosis and treatment of early oesophageal carcinomas. The database of PubMed and Medline was searched and analysed to provide all relevant literature for this review. Results and Conclusion Endoscopic resection is the therapy of choice in early oesophageal cancer. In case of adenocarcinoma it is mandatory to perform subsequent ablation of all residual Barrett's mucosa to avoid metachronous lesions. PMID:26989386

  2. A Comparison of Aphasia Therapy Outcomes before and after a Very Early Rehabilitation Programme Following Stroke

    ERIC Educational Resources Information Center

    Godecke, Erin; Ciccone, Natalie A.; Granger, Andrew S.; Rai, Tapan; West, Deborah; Cream, Angela; Cartwright, Jade; Hankey, Graeme J.

    2014-01-01

    Background: Very early aphasia rehabilitation studies have shown mixed results. Differences in therapy intensity and therapy type contribute significantly to the equivocal results. Aims: To compare a standardized, prescribed very early aphasia therapy regimen with a historical usual care control group at therapy completion (4-5 weeks post-stroke)…

  3. Early Intervention for Borderline Personality Disorder: Psychodynamic Therapy in Adolescents.

    PubMed

    Salzer, Simone; Cropp, Carola; Streeck-Fischer, Annette

    2014-01-01

    Borderline personality disorder (BPD) should be understood as a disorder of development (Streeck-Fischer 2008, 2013) that has its first manifestation in late childhood and adolescence. There are only few treatment studies of adolescents meeting the diagnostic criteria of borderline personality disorder, although early interventions for these patients are urgently needed (see Chanen & McCutcheon 2013). We examined the effectiveness of an inpatient psychodynamic therapy (PDT). Twenty-eight adolescents fulfilling the DSM-IV diagnostic criteria of borderline personality disorder were treated with psychodynamic therapy. The mean duration of treatment was 29.87 weeks (SD = 15.88). Outcomes were remission rates, GAF, GSI, SDQ, IIP and BPI scores. Assessments were made at admission and after treatment. Pre-post comparisons and comparisons with normative data were conducted. At the end of treatment 39.29% of the patients were remitted. We found significant improvements for the GAF, GSI, SDQ, IIP (all p0.001) and the BPI (p = 0.006). These clinically relevant improvements demonstrate the effectiveness of psychodynamic therapy in adolescents with borderline personality disorder and stress the usefulness of an early intervention for these patients.

  4. Causes and predictive factors of mortality in a cohort of patients with hepatitis C virus-related cryoglobulinemic vasculitis treated with antiviral therapy.

    PubMed

    Landau, Dan-Avi; Scerra, Samy; Sene, Damien; Resche-Rigon, Mathieu; Saadoun, David; Cacoub, Patrice

    2010-03-01

    Hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder with significant morbidity and mortality. Renal involvement was associated with an increased mortality, and was the most common cause of death; these data were obtained before effective antiviral treatment was available. We studied causes of death and predictive factors in patients with HCV-associated MC vasculitis treated with antivirals. Case histories of 85 patients with HCV-associated MC vasculitis treated in a single center between 1990 and 2006 were retrospectively reviewed. Prognostic factors affecting mortality were studied by comparing 23 patients who died with 62 survivors, using the Cox model regression analysis. The most common cause of death was infection, accounting for 34.7%, followed by endstage liver disease in 30.4% (including 4 patients with hepatocellular carcinoma), and cardiovascular disease in 17.4% of patients. Endstage renal disease accounted for only 8.7% of deaths, as did central nervous system vasculitis and nonhepatic malignancy. Increased mortality was strongly associated with immunosuppressive treatment [hazard ratio (HR) 6.51, 95% CI 2.75-15.37], cutaneous ulcers (HR 5.37, 95% CI 1.79-16.14), and renal insufficiency (HR 3.25, 95% CI 1.37-7.72). A 2 log10 decrease in HCV viral load at month 3 after starting antiviral treatment was associated with decreased mortality (HR 0.39, 95% CI 0.16-0.95). While renal involvement is still associated with poorer prognosis, infectious processes are now the most common cause of death in HCV cryoglobulinemia vasculitis. Immunosuppressive treatment is associated with an increased risk of death, independently from disease severity. Response to antiviral treatment is associated with significantly reduced mortality risk.

  5. Endoscopic therapy in early adenocarcinomas (Barrett's cancer) of the esophagus.

    PubMed

    Knabe, Mate; May, Andrea; Ell, Christian

    2015-07-01

    The incidence of early esophageal adenocarcinoma has been increasing significantly in recent decades. Prognosis depends greatly on the choice of treatment. Early cancers can be treated by endoscopic resection, whereas advanced carcinomas have to be sent for surgery. Esophageal resection is associated with high perioperative mortality (1-5%) even in specialized centers. Early diagnosis enables curative endoscopic treatment option. Patients with gastrointestinal symptoms and a familial risk for esophageal cancer should undergo upper gastrointestinal endoscopy. High-definition endoscopes have been developed with technical add-on that helps endoscopists to find fine irregularities in the esophageal mucosa, but interpreting the findings remains challenging. In this review we discussed novel and old diagnostic procedures and their values, as well as our own recommendations and those of the authors discussed for the diagnosis and treatment of early Barrett's carcinoma. Endoscopic resection is the therapy of choice in early esophageal adenocarcinoma. It is mandatory to perform a subsequent ablation of all residual Barrett's mucosa to avoid metachronous lesions. © 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  6. High conservation of herpes simplex virus UL5/UL52 helicase-primase complex in the era of new antiviral therapies.

    PubMed

    Collot, Marianne; Rouard, Caroline; Brunet, Christel; Agut, Henri; Boutolleau, David; Burrel, Sonia

    2016-04-01

    The emergence of herpes simplex virus (HSV) resistance to current antiviral drugs, that all target the viral DNA polymerase, constitutes a major obstacle to antiviral treatment effectiveness of HSV infections, especially in immunocompromised patients. A novel and promising class of inhibitors of the HSV UL5/UL52 helicase-primase (HP) complex has been reported to hinder viral replication with a high potency. In this study, we describe the low natural polymorphism (interstrain identity >99.1% at both nucleotide and amino acid levels) of HSV HP complex subunits pUL5 and pUL52 among 64 HSV (32 HSV-1 and 32 HSV-2) clinical isolates, and we show that the HSV resistance profile to the first-line antiviral drug acyclovir (ACV) does not impact on the natural polymorphism of HSV HP complex. Genotypic tools and polymorphism data concerning HSV HP complex provided herein will be useful to detect drug resistance mutations in a relevant time frame when HP inhibitors (HPIs), i.e., amenamevir and pritelivir, will be available in medical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study

    DOE PAGES

    Lau, George; Benhamou, Yves; Chen, Guofeng; ...

    2016-07-25

    In order to shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNAmore » <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. Furthermore, the primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and

  8. Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study

    SciTech Connect

    Lau, George; Benhamou, Yves; Chen, Guofeng

    In order to shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNAmore » <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. Furthermore, the primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and

  9. Treatment with the smallpox antiviral tecovirimat (ST-246) alone or in combination with ACAM2000 vaccination is effective as a postsymptomatic therapy for monkeypox virus infection.

    PubMed

    Berhanu, Aklile; Prigge, Jonathan T; Silvera, Peter M; Honeychurch, Kady M; Hruby, Dennis E; Grosenbach, Douglas W

    2015-07-01

    The therapeutic efficacies of smallpox vaccine ACAM2000 and antiviral tecovirimat given alone or in combination starting on day 3 postinfection were compared in a cynomolgus macaque model of lethal monkeypox virus infection. Postexposure administration of ACAM2000 alone did not provide any protection against severe monkeypox disease or mortality. In contrast, postexposure treatment with tecovirimat alone or in combination with ACAM2000 provided full protection. Additionally, tecovirimat treatment delayed until day 4, 5, or 6 postinfection was 83% (days 4 and 5) or 50% (day 6) effective. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  10. CMV Infection in Bone Marrow and Solid Organ Transplant Patients in the Era of Antiviral Prophylaxis.

    PubMed

    Hebart, Holger; Jahn, Gerhard; Sinzger, Christian; Kanz, Lothar; Einsele, Hermann

    2000-02-01

    Recent developments in the diagnosis and therapy of cytomegalovirus (CMV) infection have helped to reduce CMV-associated morbidity and mortality following allogeneic bone marrow and solid organ transplantation. The clinical symptoms of active CMV infection and the prevalence of life-threatening CMV disease vary widely between different patient populations according to the type of transplant and the intensity of immunosuppression employed. Antiviral prophylaxis with aciclovir, valaciclovir and ganciclovir has been shown to reduce CMV infection and disease following organ transplantation. Antiviral drugs, in particular ganciclovir and foscarnet, have varying sideeffects, however, and antiviral resistance due to prolonged administration of ganciclovir and foscarnet has been reported recently. Short courses of pre-emptive antiviral therapy for documented CMV infection help to reduce the duration and sideeffects of therapy, offering an alternative strategy to antiviral prophylaxis. Studies are required to compare the efficacy and costs of antiviral prophylaxis with pre-emptive therapy.

  11. Early experience with Suboxone maintenance therapy in Hungary.

    PubMed

    Demetrovics, Zsolt; Farkas, Judit; Csorba, József; Németh, Attila; Mervó, Barbara; Szemelyácz, János; Fleischmann, Enikö; Kassai-Farkas, Akos; Petke, Zsolt; Oroján, Tibor; Rózsa, Sándor; Rigó, Péter; Funk, Sándor; Kapitány, Máté; Kollár, Anna; Rácz, József

    2009-12-01

    Suboxone (Buprenorphine/naloxone) is a novel drug used in opiate substitution therapy. In Hungary, it was introduced in November 2007. Suboxone is a product for sublingual administration containing the partial mu-receptor agonist buprenorphine and antagonist naloxone in a 4:1 ratio. Objectives of our study were to monitor and evaluate the effects of Suboxone treatment. 6 outpatient centers participated in the study, 3 from Budapest and 3 from smaller cities in Hungary. At these centers, all patients entering Suboxone maintenance therapy between November 2007 and March 2008, altogether 80 persons (55 males, 35 females, mean age = 30.2 years, SD=5.48) were included in the study sample. During the 6-month period of treatment, data were collected 4 times; when entering treatment, 1 month, 3 months, and 6 months after entering treatment. Applied measures were the Addiction Severity Index, SCID-I, SCID-II, Hamilton Depression Scale, Hamilton Anxiety Scale, STAI-S State Anxiety Inventory, Beck Depression Inventory, Heroin Craving Questionnaire, WHO Well-being Inventory, Perceived Stress Scale, ADHD retrospective questionnaire, TCI short version, and Ways of Coping questionnaire. Nearly fourth of the altogether 80 heroin dependent patients (18 persons, 22.5%) dropped out of treatment during the first month (the majority, 12 persons [15%] during the first week) or chose methadone substitution instead. Following this period however, dropout rate decreased and the six-month treatment period was completed by 32 patients (40%). During the first month of treatment significant positive changes were experienced in all studied psychological and behavioral dimensions that proved to be stabile throughout the studied period. According to the early experience with Suboxone treatment, it is a well tolerable and successfully applicable drug in the substitution therapy of opiate addicts. A critical phase seems to be the first one or two weeks of treatment. Dropout rate is high during this

  12. Antiviral Perspectives for Chikungunya Virus

    PubMed Central

    Cherian, Sarah

    2014-01-01

    Chikungunya virus (CHIKV) is a mosquito-borne pathogen that has a major health impact in humans and causes acute febrile illness in humans accompanied by joint pains and, in many cases, persistent arthralgia lasting for weeks to years. CHIKV reemerged in 2005-2006 in several parts of the Indian Ocean islands and India after a gap of 32 years, causing millions of cases. The re-emergence of CHIKV has also resulted in numerous outbreaks in several countries in the eastern hemisphere, with a threat to further expand in the near future. However, there is no vaccine against CHIKV infection licensed for human use, and therapy for CHIKV infection is still mainly limited to supportive care as antiviral agents are yet in different stages of testing or development. In this review we explore the different perspectives for chikungunya treatment and the effectiveness of these treatment regimens and discuss the scope for future directions. PMID:24955364

  13. Response to Early AED Therapy and Its Prognostic Implications

    PubMed Central

    French, Jacqueline A.

    2002-01-01

    Determining the prognosis of patients when they first present with epilepsy is a difficult task. Several clinical studies have shed light on this very important topic. Potential predictors of the refractory state, including seizure etiology, duration of epilepsy before treatment, and epilepsy type, have not been successful indicators of long-term outcome. One predictor of the refractory state appears to be early response to AED therapy. Inadequate seizure control after initial treatment is a poor prognostic sign. Recent research into genetic causes of the refractory state has included investigation of the multiple drug resistance gene, and polymorphisms at drug targets. More work is needed to determine the causes and predictors of drug resistance. PMID:15309146

  14. Early and Late Onset Side Effects of Photodynamic Therapy

    PubMed Central

    Borgia, Francesco; Giuffrida, Roberta; Caradonna, Emanuela; Guarneri, Fabrizio; Cannavò, Serafinella P.

    2018-01-01

    Photodynamic Therapy (PDT) is a non-invasive treatment successfully used for neoplastic, inflammatory and infectious skin diseases. One of its strengths is represented by the high safety profile, even in elderly and/or immuno-depressed subjects. PDT, however, may induce early and late onset side effects. Erythema, pain, burns, edema, itching, desquamation, and pustular formation, often in association with each other, are frequently observed in course of exposure to the light source and in the hours/days immediately after the therapy. In particular, pain is a clinically relevant short-term complication that also reduces long-term patient satisfaction. Rare complications are urticaria, contact dermatitis at the site of application of the photosensitizer, and erosive pustular dermatosis. Debated is the relationship between PDT and carcinogenesis: the eruptive appearance of squamous cell carcinoma (SCC) in previously treated areas has been correlated to a condition of local and/or systemic immunosuppression or to the selection of PDT-resistant SCC. Here we review the literature, with particular emphasis to the pathogenic hypotheses underlying these observations. PMID:29382133

  15. Photodynamic therapy in early esophageal squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Spinelli, Pasquale; Dal Fante, Marco; Mancini, Andrea; Massetti, Renato; Meroni, Emmanuele

    1995-03-01

    From 1/1985 to 7/1993, 18 patients underwent endoscopic photodynamic therapy (PDT) for early stage esophageal squamous cell carcinoma -- as two patients had two synchronous esophageal cancers, 20 lesions were treated. Tumors were staged as Tis in 7 cases and T1 in 13. The average light energy delivered was 50 J/cm2 and 70 J/cm2 for the treatment of Tis and T1, respectively. To obtain a more uniform distribution of laser light in 12 cases the irradiation was performed through the wall of a transparent tube previously placed over the endoscope and advanced into the stomach. The overall results show a complete response in 14/20 (70%) tumors. Three patients developed a local recurrence, 6, 12, and 14 months after therapy. After a follow-up of 5 to 75 months, there was no evidence of disease in 10/18 patients (56%). The actuarial survival rate was 95%, 79%, and 26% at 1, 3, and 5 years, respectively. Complications were skin reaction in one patient and esophageal stenosis at the treatment site, that gradually responded to endoscopic bougienage, in 2 patients. Endoscopic PDT proved to be safe and effective in the treatment of superficial carcinoma of the esophagus.

  16. Early response to therapy and survival in multiple myeloma.

    PubMed

    Schaar, C G; Kluin-Nelemans, J C; le Cessie, S; Franck, P F H; te Marvelde, M C; Wijermans, P W

    2004-04-01

    Whether the response to chemotherapy is a prognosticator in multiple myeloma (MM) is still not known. Therefore, the relationship between survival and the rate of monoclonal protein (M-protein) decrement during the first cycles of therapy was prospectively assessed in 262 patients with newly diagnosed MM that were included in a phase III trial (HOVON-16). M-proteins were collected monthly during melphalan-prednisone therapy (MP: melphalan 0.25 mg/kg, prednisone 1.0 mg/kg orally for 5 d every 4 weeks). Patients with light chain disease (n = 18), immunoglobulin M (IgM)-MM (n = 1) and no immunotyping (n = 1) were excluded. Of the 242 patients studied, 75% had IgG M-protein and 25% IgA; MM stages: I: 1%, II: 35% and III: 64%. The median M-protein decrease after the first cycle of MP was 21% for IgG and 27% for IgA, and declined to < 5% after four cycles. An obvious survival advantage was seen for patients who had an M-protein decrease of at least 30% after the first MP cycle, which became significant when an M-protein decrease of 40% or more was reached. As established prognostic parameters (Salmon & Durie stage, serum creatinine, and haemoglobin) also remained prognostically significant, we concluded that early response to MP predicts for survival in MM.

  17. A concept for early cancer detection and therapy

    NASA Astrophysics Data System (ADS)

    Waynant, Ronald W.; Ilev, Ilko K.; Mitra, Kunal

    2003-06-01

    Early detection and treatment of breast cancer is least costly in terms of dollars, morbidity and mortality. With new early detection x-ray technology, tumors can be found, diagnosed and treated at a much smaller size than is currently possible. This paper proposes the development of a high resolution, high quality imaging system. It is a laser-driven x-ray system with time-gated detection that removes scattering noise in the image and produces resolution on the order of 10 μm. This higher resolution and higher image quality will enable the detection of one or two millimeter tumors hopefully detecting them before metastasis. We also propose that tumor detection should be followed by an immediate needle-directed, optical fiber biopsy to instantly determine if cancer is present and, if present, the tumor should immediately be given a lethal treatment of laser or x-radiation through the same needle using fiber optics or hollow waveguides. This technology will help prevent multiple interventions resulting in both the lowest overall cost and a more efficacious therapy. The approach can be stopped at the first negative (benign) indication and will help forestall repeated examination as well as reduce patient anxiety.

  18. The interferon response circuit in antiviral host defense.

    PubMed

    Haller, O; Weber, F

    2009-01-01

    Viruses have learned to multiply in the face of a powerful innate and adaptive immune response of the host. They have evolved multiple strategies to evade the interferon (IFN) system which would otherwise limit virus growth at an early stage of infection. IFNs induce the synthesis of a range of antiviral proteins which serve as cell-autonomous intrinsic restriction factors. For example, the dynamin-like MxA GTPase inhibits the multiplication of influenza and bunyaviruses (such as La Crosse virus, Hantaan virus, Rift Valley Fever virus, and Crimean-Congo hemorrhagic fever virus) by binding and sequestering the nucleocapsid protein into large perinuclear complexes. To overcome such intracellular restrictions, virulent viruses either inhibit IFN synthesis, bind and inactivate secreted IFN molecules, block IFN-activated signaling, or disturb the action of IFN-induced antiviral proteins. Many viruses produce specialized proteins to disarm the danger signal or express virulence genes that target members of the IFN regulatory factor family (IRFs) or components of the JAK-STAT signaling pathway. An alternative evasion strategy is based on extreme viral replication speed which out-competes the IFN response. The identification of viral proteins with IFN antagonistic functions has great implications for disease prevention and therapy. Virus mutants lacking IFN antagonistic properties represent safe yet highly immunogenic candidate vaccines. Furthermore, novel drugs intercepting viral IFN-antagonists could be used to disarm the viral intruders.

  19. Early estimation of pandemic influenza Antiviral and Vaccine Effectiveness (EAVE): use of a unique community and laboratory national data-linked cohort study.

    PubMed

    Simpson, Colin R; Lone, Nazir; McMenamin, Jim; Gunson, Rory; Robertson, Chris; Ritchie, Lewis D; Sheikh, Aziz

    2015-10-01

    After the introduction of any new pandemic influenza, population-level surveillance and rapid assessment of the effectiveness of a new vaccination will be required to ensure that it is targeted to those at increased risk of serious illness or death from influenza. We aimed to build a pandemic influenza reporting platform that will determine, once a new pandemic is under way: the uptake and effectiveness of any new pandemic vaccine or any protective effect conferred by antiviral drugs once available; the clinical attack rate of pandemic influenza; and the existence of protection provided by previous exposure to, and vaccination from, A/H1N1 pandemic or seasonal influenza/identification of susceptible groups. An observational cohort and test-negative study design will be used (post pandemic). A national linkage of patient-level general practice data from 41 Practice Team Information general practices, hospitalisation and death certification, virological swab and serology-linked data. We will study a nationally representative sample of the Scottish population comprising 300,000 patients. Confirmation of influenza using reverse transcription polymerase chain reaction and, in a subset of the population, serology. Future available pandemic influenza vaccination and antivirals will be evaluated. To build a reporting platform tailored towards the evaluation of pandemic influenza vaccination. This system will rapidly measure vaccine effectiveness (VE), adjusting for confounders, estimated by determining laboratory-confirmed influenza; influenza-related morbidity and mortality, including general practice influenza-like illnesses (ILIs); and hospitalisation and death from influenza and pneumonia. Once a validated haemagglutination inhibition assay has been developed (and prior to the introduction of any vaccination), cross-reactivity with previous exposure to A/H1N1 or A/H1N1 vaccination, other pandemic influenza or other seasonal influenza vaccination or exposure will be

  20. Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

    PubMed

    Lockhart, Pauline; Daly, Fergus; Pitkethly, Marie; Comerford, Natalia; Sullivan, Frank

    2009-10-07

    Antiviral agents against herpes simplex virus are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but their effectiveness is uncertain. Significant morbidity can be associated with severe cases. This review addresses the effect of antiviral therapy on Bell's palsy. We updated the search of the Cochrane Neuromuscular Disease Group Trials Register (December 2008), MEDLINE (from January 1966 to December 8 2008), EMBASE (from January 1980 to December 8 2008) and LILACS (from January 1982 to December 2008). Randomized trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. Twenty-three papers were selected for consideration. Seven trials including 1987 participants met the inclusion criteria, adding five studies to the two in the previous review.Incomplete recovery at one year. There was no significant benefit in the rate of incomplete recovery from antivirals compared with placebo (n = 1886, RR 0.88, 95% CI 0.65 to 1.18). In meta-analyses with some unexplained heterogeneity, the outcome with antivirals was significantly worse than with corticosteroids (n = 768, RR 2.82, 95% CI 1.09 to 7.32) and the outcome with antivirals plus corticosteroids was significantly better than with placebo (n = 658, RR 0.56, 95% CI 0.41 to 0.76).Motor synkinesis or crocodile tears at one year. In single trials, there was no significant difference in long term sequelae comparing antivirals and corticosteroids with corticosteroids alone (n = 99, RR 0.39, 95% CI 0.14 to 1.07) or antivirals with corticosteroids (n = 101, RR 1.03, 95% CI 0.51 to 2.07).Adverse events.There was no significant difference in rates of adverse events between antivirals and placebo (n = 1544, RR 1.06, 95% CI 0.81 to 1.38), between antivirals and corticosteroids (n = 667, RR 0.96, 95% CI 0.65 to 1.41) or between the antiviral-corticosteroid combination and placebo (n = 658, RR 1.15, 95% CI 0.79 to 1.66). High quality evidence showed no

  1. Efficacy and safety of an antiviral Iota-Carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold

    PubMed Central

    2010-01-01

    Background The common cold, the most prevalent contagious viral disease in humans still lacks a safe and effective antiviral treatment. Iota-Carrageenan is broadly active against respiratory viruses in-vitro and has an excellent safety profile. This study investigated the efficacy and safety of an Iota-Carrageenan nasal spray in patients with common cold symptoms. Methods In a randomized, double-blind, placebo-controlled exploratory trial, 35 human subjects suffering from early symptoms of common cold received Iota-Carrageenan (0.12%) in a saline solution three times daily for 4 days, compared to placebo. Results Administration of Iota-Carrageenan nasal spray reduced the symptoms of common cold (p = 0.046) and the viral load in nasal lavages (p = 0.009) in patients with early symptoms of common cold. Pro-inflammatory mediators FGF-2, Fractalkine, GRO, G-CSF, IL-8, IL-1α, IP-10, IL-10, and IFN-α2 were reduced in the Iota-Carrageenan group. Conclusions Iota-Carrageenan nasal spray appears to be a promising treatment for safe and effective treatment of early symptoms of common cold. Larger trials are indicated to confirm the results. PMID:20696083

  2. Efficacy and safety of an antiviral Iota-Carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold.

    PubMed

    Eccles, Ron; Meier, Christiane; Jawad, Martez; Weinmüllner, Regina; Grassauer, Andreas; Prieschl-Grassauer, Eva

    2010-08-10

    The common cold, the most prevalent contagious viral disease in humans still lacks a safe and effective antiviral treatment. Iota-Carrageenan is broadly active against respiratory viruses in-vitro and has an excellent safety profile. This study investigated the efficacy and safety of an Iota-Carrageenan nasal spray in patients with common cold symptoms. In a randomized, double-blind, placebo-controlled exploratory trial, 35 human subjects suffering from early symptoms of common cold received Iota-Carrageenan (0.12%) in a saline solution three times daily for 4 days, compared to placebo. Administration of Iota-Carrageenan nasal spray reduced the symptoms of common cold (p = 0.046) and the viral load in nasal lavages (p = 0.009) in patients with early symptoms of common cold. Pro-inflammatory mediators FGF-2, Fractalkine, GRO, G-CSF, IL-8, IL-1alpha, IP-10, IL-10, and IFN-alpha2 were reduced in the Iota-Carrageenan group. Iota-Carrageenan nasal spray appears to be a promising treatment for safe and effective treatment of early symptoms of common cold. Larger trials are indicated to confirm the results.

  3. Safety of Direct-Acting Antiviral Therapy Regarding Renal Function in Post-Liver Transplant Patients Infected with Hepatitis C Virus and a 100% 12-Week Sustained Virologic Response-A Single-Center Study.

    PubMed

    Peschel, G; Moleda, L; Baier, L; Selgrad, M; Schmid, S; Scherer, M N; Müller, M; Weigand, K

    2018-06-01

    Patients after liver transplantation (LT) with hepatitis C virus (HCV) infection often suffer from renal or hepatic impairment. Treating patients after LT with direct-acting antivirals (DAA) might result in decreasing renal function due to interaction of DAA and immunosuppressive therapy. In this single-center study we analyzed clinical parameters of 18 HCV-infected patients treated with DAA therapy after LT. The primary end points were change of renal function (glomerular filtration rate) and sustained virologic response 12 weeks after therapy (SVR12). For secondary end points, we investigated the influence of DAA therapy on transaminases, bilirubin, international normalized ratio, noninvasive fibrosis measurement, and Model for End-Stage Liver Disease (MELD) score. Five out of 18 patients treated with DAA suffered from renal impairment stage 2, and 7 patients of renal impairment stage 3. Renal function at SVR12 was not influenced by preexisting renal impairment (P > .5), type of immunosuppressant (P > .5), or type of DAA regimen (P > .5). All patients reached SVR12. The levels of transaminases and bilirubin declined rapidly, as expected. Ten out of 18 patients already suffered from cirrhosis or liver fibrosis >F3 according to noninvasive measurement before initiation of treatment. Single-point acoustic radiation force impulse imaging improved in 9 patients (P = .012). In 7 patients, MELD score improved owing to the decrease of bilirubin levels. In 6 patients it worsened. DAA therapy in LT patients was effective and safe in this single-center real-life cohort. Renal function was not influenced by the administered drug combinations, even in patients with preexisting renal impairment. Copyright © 2018. Published by Elsevier Inc.

  4. Evidence for a Dual Antiviral Role of the Major Nuclear Domain 10 Component Sp100 during the Immediate-Early and Late Phases of the Human Cytomegalovirus Replication Cycle ▿

    PubMed Central

    Tavalai, Nina; Adler, Martina; Scherer, Myriam; Riedl, Yvonne; Stamminger, Thomas

    2011-01-01

    In recent studies, the nuclear domain 10 (ND10) components PML and hDaxx were identified as cellular restriction factors that inhibit the initiation of human cytomegalovirus (HCMV) replication. The antiviral function of ND10, however, is antagonized by the IE1 protein, which induces ND10 disruption. Here we show that IE1 not only de-SUMOylates PML immediately upon infection but also directly targets Sp100. IE1 expression alone was sufficient to downregulate endogenous Sp100 independently of the presence of PML. Moreover, cotransfection experiments revealed that IE1 negatively interferes with the SUMOylation of all Sp100 isoforms. The modulation of Sp100 at immediate-early (IE) times of infection, indeed, seemed to have an in vivo relevance for HCMV replication, since knockdown of Sp100 resulted in more cells initiating the viral gene expression program. In addition, we observed that Sp100 was degraded in a proteasome-dependent manner at late times postinfection, suggesting that Sp100 may play an additional antiviral role during the late phase. Infection experiments conducted with Sp100 knockdown human foreskin fibroblasts (HFFs) confirmed this hypothesis: depletion of Sp100 resulted in augmented release of progeny virus particles compared to that from control cells. Consistent with this observation, we noted increased amounts of viral late gene products in the absence of Sp100. Importantly, this elevated late gene expression was not dependent on enhanced viral IE gene expression. Taken together, our data provide evidence that Sp100 is the first ND10-related factor identified that not only possesses the potential to restrict the initial stage of infection but also inhibits HCMV replication during the late phase. PMID:21734036

  5. WITHDRAWN. Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

    PubMed

    Gagyor, Ildiko; Madhok, Vishnu B; Daly, Fergus; Somasundara, Dhruvashree; Sullivan, Michael; Gammie, Fiona; Sullivan, Frank

    2015-05-04

    Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains. Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. Eleven trials, including 2883 participants, met the inclusion criteria and are included in the final analysis. We added four studies to the previous review for this update. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recoveryWe found no significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.47 to 1.02, n = 1715). For people with severe Bell's palsy (House-Brackmann scores of 5 and 6 or the equivalent in other scales), we found a reduction in the rate of incomplete recovery at month six when antivirals plus corticosteroids were used (RR 0.64, 95% CI 0.41 to 0

  6. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis.

    PubMed

    Wallace, Carol A; Giannini, Edward H; Spalding, Steven J; Hashkes, Philip J; O'Neil, Kathleen M; Zeft, Andrew S; Szer, Ilona S; Ringold, Sarah; Brunner, Hermine I; Schanberg, Laura E; Sundel, Robert P; Milojevic, Diana; Punaro, Marilynn G; Chira, Peter; Gottlieb, Beth S; Higgins, Gloria C; Ilowite, Norman T; Kimura, Yukiko; Hamilton, Stephanie; Johnson, Anne; Huang, Bin; Lovell, Daniel J

    2012-06-01

    To determine whether aggressive treatment initiated early in the course of rheumatoid factor (RF)-positive or RF-negative polyarticular juvenile idiopathic arthritis (JIA) can induce clinical inactive disease within 6 months. Between May 2007 and October 2010, a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 2 aggressive treatments was conducted in 85 children ages 2-16 years with polyarticular JIA of <12 months' duration. Patients received either methotrexate (MTX) 0.5 mg/kg/week (maximum 40 mg) subcutaneously, etanercept 0.8 mg/kg/week (maximum 50 mg), and prednisolone 0.5 mg/kg/day (maximum 60 mg) tapered to 0 by 17 weeks (arm 1), or MTX (same dosage as arm 1), etanercept placebo, and prednisolone placebo (arm 2). The primary outcome measure was clinical inactive disease at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous clinical inactive disease) at 12 months. By 6 months, clinical inactive disease had been achieved in 17 (40%) of 42 patients in arm 1 and 10 (23%) of 43 patients in arm 2 (χ(2) = 2.91, P = 0.088). After 12 months, clinical remission on medication was achieved in 9 patients in arm 1 and 3 patients in arm 2 (P = 0.053). There were no significant interarm differences in adverse events. Although this study did not meet its primary end point, early aggressive therapy in this cohort of children with recent-onset polyarticular JIA resulted in clinical inactive disease by 6 months and clinical remission on medication within 12 months of treatment in substantial proportions of patients in both arms. Copyright © 2012 by the American College of Rheumatology.

  7. Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis

    PubMed Central

    Wallace, Carol A.; Giannini, Edward H.; Spalding, Steven J.; Hashkes, Philip J.; O’Neil, Kathleen M.; Zeft, Andrew S.; Szer, Ilona S.; Ringold, Sarah; Brunner, Hermine I.; Schanberg, Laura E.; Sundel, Robert P.; Milojevic, Diana; Punaro, Marilynn G.; Chira, Peter; Gottlieb, Beth S.; Higgins, Gloria C.; Ilowite, Norman T.; Kimura, Yukiko; Hamilton, Stephanie; Johnson, Anne; Huang, Bin; Lovell, Daniel J.

    2011-01-01

    OBJECTIVES To determine if aggressive treatment initiated early in the course of rheumatoid factor positive or negative polyarticular juvenile idiopathic arthritis (poly-JIA) can induce clinical inactive disease (CID) within 6 months. METHODS Between May 2007 and October 2010 a multi-center, prospective, double blind, randomized, placebo controlled trial of two aggressive treatments was conducted in 85 children aged 2 to 16 years with polyarticular JIA of less than 12 months duration. Patients received either methotrexate 0.5 mg/kg/wk SQ (40 mg max), etanercept 0.8 mg/kg/wk (50 mg max), prednisolone 0.5 mg/kg/d (60 mg max) tapered to 0 by 17 weeks (Arm 1), or methotrexate (same dose as Arm 1), etanercept placebo, and prednisolone placebo (Arm 2). The primary outcome was CID at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous CID) at 12 months. RESULTS By 6 months, 17 of 42 (40%) of patients in Arm 1 and 10 of 43 (23%) in Arm 2 had achieved CID (X2 = 2.91; p = 0.088). After 12 months, 9 patients in Arm 1 and 3 in Arm 2 achieved clinical remission on medication (p = 0.0534). There were no significant inter-arm differences in adverse events. CONCLUSIONS Although this study did not meet its primary endpoint, early aggressive therapy in this cohort of children with recent onset polyarticular JIA resulted in substantial proportions of patients in both arms achieving CID by 6 months and clinical remission on medication within 12 months of treatment. PMID:22183975

  8. Photodynamic therapy (PDT) utilizing PhotofrinR for treatment of early esophageal cancer

    NASA Astrophysics Data System (ADS)

    Overholt, Bergein F.; Panjehpour, Masoud; Teffeteller, Elmeria; Rose, S. Mark

    1993-06-01

    Four lesions of early carcinoma of the esophagus found during endoscopic biopsies in three patients were treated with photodynamic therapy. Follow-up biopsies over 9 - 24 months remain negative for carcinoma. Endoscopic ultrasonography is essential for proper staging and treatment planning for these patients. Photodynamic therapy may provide an alternative to surgical resection for early esophageal carcinoma or severe dysplasia in Barrett's esophagus.

  9. Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing

    NASA Astrophysics Data System (ADS)

    Takeda, Haruhiko; Ueda, Yoshihide; Inuzuka, Tadashi; Yamashita, Yukitaka; Osaki, Yukio; Nasu, Akihiro; Umeda, Makoto; Takemura, Ryo; Seno, Hiroshi; Sekine, Akihiro; Marusawa, Hiroyuki

    2017-03-01

    Resistance-associated variant (RAV) is one of the most significant clinical challenges in treating HCV-infected patients with direct-acting antivirals (DAAs). We investigated the viral dynamics in patients receiving DAAs using third-generation sequencing technology. Among 283 patients with genotype-1b HCV receiving daclatasvir + asunaprevir (DCV/ASV), 32 (11.3%) failed to achieve sustained virological response (SVR). Conventional ultra-deep sequencing of HCV genome was performed in 104 patients (32 non-SVR, 72 SVR), and detected representative RAVs in all non-SVR patients at baseline, including Y93H in 28 (87.5%). Long contiguous sequences spanning NS3 to NS5A regions of each viral clone in 12 sera from 6 representative non-SVR patients were determined by third-generation sequencing, and showed the concurrent presence of several synonymous mutations linked to resistance-associated substitutions in a subpopulation of pre-existing RAVs and dominant isolates at treatment failure. Phylogenetic analyses revealed close genetic distances between pre-existing RAVs and dominant RAVs at treatment failure. In addition, multiple drug-resistant mutations developed on pre-existing RAVs after DCV/ASV in all non-SVR cases. In conclusion, multi-drug resistant viral clones at treatment failure certainly originated from a subpopulation of pre-existing RAVs in HCV-infected patients. Those RAVs were selected for and became dominant with the acquisition of multiple resistance-associated substitutions under DAA treatment pressure.

  10. Management of early renal anaemia: diagnostic work-up, iron therapy, epoetin therapy.

    PubMed

    Van Wyck, D B

    2000-01-01

    Effective management of early anaemia in the course of chronic renal insufficiency requires the following: (i) implementing an efficient diagnostic strategy to exclude common contributing factors; (ii) initiating epoetin therapy for the majority of patients; for and (iii) ensuring adequate iron supply erythropoiesis. Diagnostic inquiry is warranted whenever the haemoglobin concentration is below the normal range adjusted for age and gender. The most efficient diagnostic approach is to assume erythropoietin deficiency, exclude iron deficiency, and pursue further diagnostic tests only when red-cell indices are abnormal or when leukopenia or thrombocytopenia are also present. Macrocytosis should prompt an inquiry into alcoholism, B12 deficiency, or folate deficiency. Microcytosis suggests iron deficiency or thalassaemia. Associated cytopenias raise the possibility of alcohol toxicity, pernicious anaemia, malignancy, or myelodysplastic syndrome. Epoetin therapy is warranted whenever the haemoglobin concentration has fallen below 10.0 g/dl. To initiate therapy prior to dialysis, epoetin should be administered at an average dose of 100 IU/kg/week (80-120 IU/kg/week, 50-150 IU/kg/ week) by subcutaneous injection. Haemoglobin concentration should be monitored every 2 weeks and the epoetin dose adjusted by increments or decrements of 25% to maintain a rate of rise of haemoglobin concentration of 0.2-0.6 g/dl (0.3 0.6 g/dl/week, 0.2-0.5 g/dl/week). When the target range is achieved, the dose of epoetin should be continually adjusted to maintain a stable haemoglobin concentration. Transferrin saturation and ferritin concentration should be monitored monthly, and sufficient iron provided to maintain transferrin saturation above 20%. The lower the haemoglobin concentration, the greater the likelihood that future intravenous iron will be required. Oral iron supplements should be avoided, since they are costly, ineffective, and troublesome to patients. Finally, a blunted

  11. Couple Therapy with Veterans: Early Improvements and Predictors of Early Dropout.

    PubMed

    Fischer, Melanie S; Bhatia, Vickie; Baddeley, Jenna L; Al-Jabari, Rawya; Libet, Julian

    2017-07-28

    Family services within Veterans Affairs Medical Centers fulfill an important role in addressing relationship distress among Veterans, which is highly prevalent and comorbid with psychopathology. However, even for evidence-based couple therapies, effectiveness is weaker compared to controlled studies, maybe because many Veteran couples drop out early and do not reach the "active" treatment stage after the 3-4 session assessment. In order to improve outcomes, it is critical to identify couples at high risk for early dropout, and understand whether couples may benefit from the assessment as an intervention. The current study examined (a) demographics, treatment delivery mode, relationship satisfaction, and psychological symptoms as predictors of dropout during and immediately following the assessment phase, and (b) changes in relationship satisfaction during assessment. 174 couples completed questionnaires during routine intake procedures. The main analyses focused on 140 male Veterans and their female civilian partners; 36.43% dropped out during the assessment phase and 24.74% of the remaining couples immediately following the first treatment session. More severe depressive symptoms in non-Veteran partners were associated with dropout during assessment. Relationship satisfaction improved significantly during the assessment phase for couples who did not drop out, with larger gains for non-Veteran partners. No demographics or treatment delivery mode were associated with dropout. Although more research is needed on engaging couples at risk for early dropout and maximizing early benefits, the findings suggest that clinicians should attend to the civilian partner's and Veteran's depressive symptoms at intake and consider the assessment part of active treatment. © 2017 Family Process Institute.

  12. Early Therapeutic Alliance and Treatment Outcome in Individual and Family Therapy for Adolescent Behavior Problems

    ERIC Educational Resources Information Center

    Hogue, Aaron; Dauber, Sarah; Stambaugh, Leyla Faw; Cecero, John J.; Liddle, Howard A.

    2006-01-01

    The impact of early therapeutic alliance was examined in 100 clients receiving either individual cognitive-behavioral therapy (CBT) or family therapy for adolescent substance abuse. Observational ratings of adolescent alliance in CBT and adolescent and parent alliance in family therapy were used to predict treatment retention (in CBT only) and…

  13. The Race To Find Antivirals for Zika Virus

    PubMed Central

    2017-01-01

    ABSTRACT Zika virus (ZIKV), a flavivirus transmitted by mosquitoes, was an almost neglected pathogen until its introduction in the Americas in 2015 and its subsequent explosive spread throughout the continent, where it has infected millions of people. The virus has caused social and sanitary alarm, mainly due to its association with severe neurological disorders (Guillain-Barré syndrome and microcephaly in fetuses and newborns). Nowadays, no specific antiviral therapy against ZIKV is available. However, during the past months, a great effort has been made to search for antiviral candidates using different approaches and methodologies, ranging from testing specific compounds with known antiviral activity to the screening of libraries with hundreds of bioactive molecules. The identified antiviral candidates include drugs targeting viral components as well as cellular ones. Here, an updated review of what has been done in this line is presented. PMID:28348160

  14. Re-recognizing serological change patterns and antiviral therapy opportunity of patients with acute hepatitis B through highly sensitive detection technology.

    PubMed

    Ma, Haixia; Gao, Min; Li, Jia; Zhou, Li; Guo, Jie; Liu, Junjuan; Han, Xu; Zhai, Lu; Wu, Ting

    2016-11-01

    This study was conducted to re-recognize serological change patterns of patients with acute hepatitis B (AHB) by a highly sensitive detection technology, as well as to explore methods to select the optimal treatment opportunity. The biochemical and virological parameters of 558 AHB patients were analyzed retrospectively. The serological markers of hepatitis B virus and HBV DNA were detected by electrochemiluminescence immunoassay and automatic real-time fluorescent quantitative PCR, respectively. At baseline, the positive rate of hepatitis B surface antigen (HBsAg) (86.2%) was significantly higher than the positive rate of HBV DNA (51.9%). Among the 58 patients with HBsAg-negative AHB, 16 were detected with trace amounts of HBV DNA at baseline. At 12 weeks, the HBsAg of 43 cases remained positive, and the mean level of HBsAg was 587.5IU/mL±313.4IU/mL. A total of 18 patients with HBsAg levels greater than 1500IU/mL at 12 weeks received interferon α-1b treatment and achieved HBsAg clearance within 24 weeks. Unlike traditional changing patterns, the clearance of HBV DNA in peripheral circulation for a few patients with AHB occurred later than HBsAg clearance. Detection of HBV DNA in peripheral circulation by highly sensitive detection technology could provide a diagnostic basis for those AHB patients who rapidly achieved HBsAg clearance before achieving HBV DNA clearance in their peripheral circulation and prevent misdiagnosis. Dynamic monitoring of the changes in HBsAg levels through highly sensitive detection technology could be used as a guide for the timely adoption of antiviral treatment with interferon and then AHB chronicity would be prevented. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Ventilatory gas exchange and early response to cardiac resynchronization therapy.

    PubMed

    Kim, Chul-Ho; Olson, Lyle J; Shen, Win K; Cha, Yong-Mei; Johnson, Bruce D

    2015-11-01

    Cardiac resynchronization therapy (CRT) is an accepted intervention for chronic heart failure (HF), although approximately 30% of patients are non-responders. The purpose of this study was to determine whether exercise respiratory gas exchange obtained before CRT implantation predicts early response to CRT. Before CRT implantation, patients were assigned to either a mild-moderate group (Mod G, n = 33, age 67 ± 10 years) or a moderate-severe group (Sev G, n = 31, age 67 ± 10 years), based on abnormalities in exercise gas exchange. Severity of impaired gas exchange was based on a score from the measures of VE/VCO(2) slope, resting PETCO(2) and change of PETCO(2) from resting to peak. All measurements were performed before and 3 to 4 months after CRT implantation. Although Mod G did not have improved gas exchange (p > 0.05), Sev G improved significantly (p < 0.05) post-CRT. In addition, Mod G did not show improved right ventricular systolic pressure (RSVP; pre vs post: 37 ± 14 vs 36 ± 11 mm Hg, p > 0.05), yet Sev G showed significantly improved RVSP, by 23% (50 ± 14 vs 42 ± 12 mm Hg, p < 0.05). Both groups had improved left ventricular ejection fraction (p < 0.05), New York Heart Association class (p < 0.05) and quality of life (p < 0.05), but no significant differences were observed between groups (p > 0.05). No significant changes were observed in brain natriuretic peptide in either group post-CRT. Based on pre-CRT implantation ventilatory gas exchange, subjects with the most impaired values appeared to have more improvement post-CRT, possibly associated with a decrease in RVSP. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  16. [Vojta's method as the early neurodevelopmental diagnosis and therapy concept].

    PubMed

    Banaszek, Grazyna

    2010-01-01

    Vaclav Vojta (1917-2000) developed an early diagnostic method of the neurodevelopmental disorder of infants and came up with therapeutic concept consisting in releasing of global motor complexes by means of the stimulation of proper areas on patients body. In the diagnostics apart from very careful observation of the spontaneous movement of the infant and examination of the reflexes that are characteristic for the first weeks of human's life, Vojta applied the examination of the 7 postural reactions. Presence of the trouble in patterns and dynamics of the postural reactions Vojta called Central Nervous Coordination Disorder--CNCD and regarded as work diagnosis or alarm signal indicating necessity of application of the therapy, especially when asymmetry of the muscle tone and primitive reflexes beyond their physiological appearance period are observed or the number of the abnormal reactions exceeds 5. Global motor complexes as reflex locomotion--crawling and rotation--consist of all the partial motion patterns, which are gradually used by healthy infant in the process of postural and motor ontogenesis. Providing the central nervous system with proper external stimulation allows to, using neuronal plasticity, recreate an access to the human's postural development program and gradually replace pathological motor patterns by those more regular. Exercises repeated several times a day rebuilt support, erectile and vertical mechanisms, improve automatic postural control and phase lower limb movement. Affecting especially on autochtonic muscles of the spine exercises balance synergic cooperation of muscle groups in the trunk and those surrounding key body joints. This way they correct body's posture and peripheral motion and pathology of the outlasted primitive reflexes gradually withdraws.

  17. Acceptability of Early Antiretroviral Therapy Among South African Women.

    PubMed

    Garrett, Nigel; Norman, Emily; Leask, Kerry; Naicker, Nivashnee; Asari, Villeshni; Majola, Nelisile; Karim, Quarraisha Abdool; Karim, Salim S Abdool

    2018-03-01

    WHO guidelines recommend immediate initiation of antiretroviral therapy (ART) for all individuals at HIV diagnosis regardless of CD4 count, but concerns remain about potential low uptake or poor adherence among healthy patients with high CD4 counts, especially in resource-limited settings. This study assessed the acceptability of earlier treatment among HIV-positive South African women, median age at enrollment 25 (IQR 22-30), in a 10 year prospective cohort study by (i) describing temporal CD4 count trends at initiation in relation to WHO guidance, (ii) virological suppression rates post-ART initiation at different CD4 count thresholds, and (iii) administration of a standardized questionnaire. 158/232 (68.1%) participants initiated ART between 2006 and 2015. Mean CD4 count at initiation was 217 cells/µl (range 135-372) before 2010, and increased to 531 cells/µl (range 272-1095) by 2015 (p < 0.001). Median viral load at ART initiation decreased over this period from 5.2 (IQR 4.6-5.6) to 4.1 (IQR 3.4-4.6) log copies/ml (p = 0.004). Virological suppression rates at 3, 6, 12 and 18 months were consistently above 85% with no statistically significant differences for participants starting ART at different CD4 count thresholds. A questionnaire assessing uptake of early ART amongst ART-naïve women, median age 28 (IQR 24-33), revealed that 40/51 (78.4%) were willing to start ART at CD4 ≥500. Of those unwilling, 6/11 (54.5%) started ART within 6 months of questionnaire administration. Temporal increases in CD4 counts, comparable virological suppression rates, and positive patient perceptions confirm high acceptability of earlier ART initiation for the majority of patients.

  18. Can we predict failure in couple therapy early enough to enhance outcome?

    PubMed

    Pepping, Christopher A; Halford, W Kim; Doss, Brian D

    2015-02-01

    Feedback to therapists based on systematic monitoring of individual therapy progress reliably enhances therapy outcome. An implicit assumption of therapy progress feedback is that clients unlikely to benefit from therapy can be detected early enough in the course of therapy for corrective action to be taken. To explore the possibility of using feedback of therapy progress to enhance couple therapy outcome, the current study tested whether weekly therapy progress could detect off-track clients early in couple therapy. In an effectiveness trial of couple therapy, 136 couples were monitored weekly on relationship satisfaction and an expert derived algorithm was used to attempt to predict eventual therapy outcome. As expected, the algorithm detected a significant proportion of couples who did not benefit from couple therapy at Session 3, but prediction was substantially improved at Session 4 so that eventual outcome was accurately predicted for 70% of couples, with little improvement of prediction thereafter. More sophisticated algorithms might enhance prediction accuracy, and a trial of the effects of therapy progress feedback on couple therapy outcome is needed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Early transition to oral antibiotic therapy for community-acquired pneumonia: duration of therapy, clinical outcomes, and cost analysis.

    PubMed

    Omidvari, K; de Boisblanc, B P; Karam, G; Nelson, S; Haponik, E; Summer, W

    1998-08-01

    Our objective was to compare therapeutic outcome and analyse cost-benefit of a 'conventional' (7-day course of i.v. antibiotic therapy) vs. an abbreviated (2-day i.v. antibiotic course followed by 'switch' to oral antibiotics) therapy for in-patients with community-acquired pneumonia (CAP). We used a multicenter prospective, randomized, parallel group with a 28 day follow-up, at the University-based teaching hospitals: The Medical Center of Louisiana in New Orleans, LA and hospitals listed in the acknowledgement. Ninety-five patients were randomized to receive either a 'conventional' course of intravenous antibiotic therapy with cefamandole 1 g i.v. every 6 h for 7 days (n = 37), or an abbreviated course of intravenous therapy with cefamandole (1 g i.v. every 6 h for 2 days) followed by oral therapy with cefaclor (500 mg every 8 h for 5 days). No difference was found in the clinical courses, cure rates, survival or the resolution of the chest radiograph abnormalities among the two groups. The mean duration of therapy (6.88 days for the conventional group compared to 7-30 days for the early oral therapy group) and the frequencies of overall symptomatic improvement (97% vs. 95%, respectively) were similar in both groups. Patients who received early oral therapy had shorter hospital stays (7.3 vs. 9.71 days, P = 0.01), and a lower total cost of care ($2953 vs. $5002, P < 0.05). It was concluded that early transition to an oral antibiotic after an abbreviated course of intravenous therapy in CAP is substantially less expensive and has comparable efficacy to conventional intravenous therapy. Altering physicians' customary management of hospitalized patients with CAP can reduce costs with no appreciable additional risk of adverse patient outcome.

  20. Intratumoral INF-γ triggers an antiviral state in GL261 tumor cells: a major hurdle to overcome for oncolytic vaccinia virus therapy of cancer.

    PubMed

    Kober, Christina; Weibel, Stephanie; Rohn, Susanne; Kirscher, Lorenz; Szalay, Aladar A

    2015-01-01

    Oncolytic vaccinia virus (VACV) therapy is an alternative treatment option for glioblastoma multiforme. Here, we used a comparison of different tumor locations and different immunologic and genetic backgrounds to determine the replication efficacy and oncolytic potential of the VACV LIVP 1.1.1, an attenuated wild-type isolate of the Lister strain, in murine GL261 glioma models. With this approach, we expected to identify microenvironmental factors, which may be decisive for failure or success of oncolytic VACV therapy. We found that GL261 glioma cells implanted subcutaneously or orthotopically into Balb/c athymic, C57BL/6 athymic, or C57BL/6 wild-type mice formed individual tumors that respond to oncolytic VACV therapy with different outcomes. Surprisingly, only Balb/c athymic mice with subcutaneous tumors supported viral replication. We identified intratumoral IFN-γ expression levels that upregulate MHCII expression on GL261 cells in C57BL/6 wild-type mice associated with a non-permissive status of the tumor cells. Moreover, this IFN-γ-induced tumor cell phenotype was reversible.

  1. Perspective of Use of Antiviral Peptides against Influenza Virus

    PubMed Central

    Skalickova, Sylvie; Heger, Zbynek; Krejcova, Ludmila; Pekarik, Vladimir; Bastl, Karel; Janda, Jozef; Kostolansky, Frantisek; Vareckova, Eva; Zitka, Ondrej; Adam, Vojtech; Kizek, Rene

    2015-01-01

    The threat of a worldwide influenza pandemic has greatly increased over the past decade with the emergence of highly virulent avian influenza strains. The increased frequency of drug-resistant influenza strains against currently available antiviral drugs requires urgent development of new strategies for antiviral therapy, too. The research in the field of therapeutic peptides began to develop extensively in the second half of the 20th century. Since then, the mechanisms of action for several peptides and their antiviral prospect received large attention due to the global threat posed by viruses. Here, we discussed the therapeutic properties of peptides used in influenza treatment. Peptides with antiviral activity against influenza can be divided into three main groups. First, entry blocker peptides such as a Flupep that interact with influenza hemagglutinin, block its binding to host cells and prevent viral fusion. Second, several peptides display virucidal activity, disrupting viral envelopes, e.g., Melittin. Finally, a third set of peptides interacts with the viral polymerase complex and act as viral replication inhibitors such as PB1 derived peptides. Here, we present a review of the current literature describing the antiviral activity, mechanism and future therapeutic potential of these influenza antiviral peptides. PMID:26492266

  2. New advances in focal therapy for early stage prostate cancer.

    PubMed

    Tay, Kae Jack; Schulman, Ariel A; Sze, Christina; Tsivian, Efrat; Polascik, Thomas J

    2017-08-01

    Prostate focal therapy offers men the opportunity to achieve oncological control while preserving sexual and urinary function. The prerequisites for successful focal therapy are to accurately identify, localize and completely ablate the clinically significant cancer(s) within the prostate. We aim to evaluate the evidence for current and upcoming technologies that could shape the future of prostate cancer focal therapy in the next five years. Areas covered: Current literature on advances in patient selection using imaging, biopsy and biomarkers, ablation techniques and adjuvant treatments for focal therapy are summarized. A literature search of major databases was performed using the search terms 'focal therapy', 'focal ablation', 'partial ablation', 'targeted ablation', 'image guided therapy' and 'prostate cancer'. Expert commentary: Advanced radiological tools such as multiparametric magnetic resonance imaging (mpMRI), multiparametric ultrasound (mpUS), prostate-specific-membrane-antigen positron emission tomography (PSMA-PET) represent a revolution in the ability to understand cancer function and biology. Advances in ablative technologies now provide a menu of modalities that can be rationalized based on lesion location, size and perhaps in the near future, pre-determined resistance to therapy. However, these need to be carefully studied to establish their safety and efficacy parameters. Adjuvant strategies to enhance focal ablation are under development.

  3. Extracorporeal Shock Wave Therapy Suppresses the Early Proinflammatory Immune Response to a Severe Cutaneous Burn Injury

    DTIC Science & Technology

    2009-02-01

    Burn wound model Mice were anaesthetised using isoflurane inha- lation. After shaving the dorsum, the exposed skin was washed gently with room...Extracorporeal shock wave therapy suppresses the early proinflammatory immune response to a severe cutaneous burn injury* Thomas A Davis, Alexander...S, Peoples GE, Tadaki D, Elster EA. Extracorporeal shock wave therapy suppresses the early proinflammatory immune response to a severe cutaneous burn

  4. Occupational Therapy Contributions in Early Intervention: Implications for Personnel Preparation and Interprofessional Practice

    ERIC Educational Resources Information Center

    Muhlenhaupt, Mary; Pizur-Barnekow, Kris; Schefkind, Sandra; Chandler, Barbara; Harvison, Neil

    2015-01-01

    Occupational therapy provides a unique contribution in early intervention programs for families and their children from birth to 3 years old who are at risk for, or who have, identified disabilities. This article describes occupational therapy's distinct value and presents the profession's perspective on services to enhance families' caregiving…

  5. Family Attachment Narrative Therapy: Healing the Experience of Early Childhood Maltreatment

    ERIC Educational Resources Information Center

    May, Joanne C.

    2005-01-01

    Based on attachment theory and research, Family Attachment Narrative Therapy is introduced as a new family therapy modality developed to heal the experience of early childhood maltreatment. Unresolved childhood trauma has been correlated with impaired and delayed cognitive, behavioral and emotional functioning. Gentle, soothing, nonprovocative and…

  6. Diagnosis and antiviral intervention strategies for mitigating an influenza epidemic.

    PubMed

    Moss, Robert; McCaw, James M; McVernon, Jodie

    2011-02-04

    Many countries have amassed antiviral stockpiles for pandemic preparedness. Despite extensive trial data and modelling studies, it remains unclear how to make optimal use of antiviral stockpiles within the constraints of healthcare infrastructure. Modelling studies informed recommendations for liberal antiviral distribution in the pandemic phase, primarily to prevent infection, but failed to account for logistical constraints clearly evident during the 2009 H1N1 outbreaks. Here we identify optimal delivery strategies for antiviral interventions accounting for logistical constraints, and so determine how to improve a strategy's impact. We extend an existing SEIR model to incorporate finite diagnostic and antiviral distribution capacities. We evaluate the impact of using different diagnostic strategies to decide to whom antivirals are delivered. We then determine what additional capacity is required to achieve optimal impact. We identify the importance of sensitive and specific case ascertainment in the early phase of a pandemic response, when the proportion of false-positive presentations may be high. Once a substantial percentage of ILI presentations are caused by the pandemic strain, identification of cases for treatment on syndromic grounds alone results in a greater potential impact than a laboratory-dependent strategy. Our findings reinforce the need for a decentralised system capable of providing timely prophylaxis. We address specific real-world issues that must be considered in order to improve pandemic preparedness policy in a practical and methodologically sound way. Provision of antivirals on the scale proposed for an effective response is infeasible using traditional public health outbreak management and contact tracing approaches. The results indicate to change the transmission dynamics of an influenza epidemic with an antiviral intervention, a decentralised system is required for contact identification and prophylaxis delivery, utilising a range of

  7. Non-invasive assessment of liver fibrosis progression in hepatitis C patients retreated for 96 weeks with antiviral therapy: a randomized study.

    PubMed

    Zarski, Jean-Pierre; Sturm, Nathalie; Desmorat, Hervé; Melin, Pascal; Raabe, Jean-Jacques; Bonny, Corinne; Sogni, Philippe; Pinta, Alexandrina; Rouanet, Stéphanie; Babany, Gérard; Cheveau, Alice; Chevallier, Michèle

    2010-08-01

    The efficacy of a maintenance therapy in non-responder patients with chronic hepatitis C has been essentially evaluated by histological semiquantitative scores. The aim was to evaluate the efficiency of 2 years of treatment with peginterferon alpha-2a vs alpha-tocopherol in these patients by histology, morphometry and blood markers of fibrosis. Hundred and five HCV patients with a Metavir fibrosis score > or = 2 were randomized to receive peginterferon alpha-2a 180 microg/week (PEG) (n=55) or alpha-tocopherol (TOCO) 1000 mg/day (n=50) for 96 weeks. The primary endpoint was improvement or stabilization of the Metavir fibrosis score by biopsy performed at week 96. Secondary endpoints included a quantitative assessment of fibrosis by morphometry and changes in blood markers of fibrosis. There was no difference at baseline between PEG and TOCO according to the metavir (83.3 vs 86.8%, P=0.751) stage. The median fibrosis rate, measured with morphometry was 2.72 and 2.86% at day 0, and 3.66 and 2.82% at week 96, in the PEG and TOCO groups (P=0.90) respectively. However, the percentage of patients with metavir activity grade improvement was significantly higher in the PEG group vs the TOCO group (52.8 vs 23.7%, P=0.016). Non-invasive markers analysis did not show any significant change in both groups. Long-term therapy with peginterferon alpha-2a did not reduce liver fibrosis degree assessed by morphometry and blood tests as compared with alpha-tocopherol. Blood tests could be useful to assess liver fibrosis changes in clinical trials.

  8. Antiviral drug research proposal activity.

    PubMed

    Injaian, Lisa; Smith, Ann C; Shipley, Jennifer German; Marbach-Ad, Gili; Fredericksen, Brenda

    2011-01-01

    The development of antiviral drugs provides an excellent example of how basic and clinical research must be used together in order to achieve the final goal of treating disease. A Research Oriented Learning Activity was designed to help students to better understand how basic and clinical research can be combined toward a common goal. Through this project students gained a better understanding of the process of scientific research and increased their information literacy in the field of virology. The students worked as teams to research the many aspects involved in the antiviral drug design process, with each student becoming an "expert" in one aspect of the project. The Antiviral Drug Research Proposal (ADRP) culminated with students presenting their proposals to their peers and local virologists in a poster session. Assessment data showed increased student awareness and knowledge of the research process and the steps involved in the development of antiviral drugs as a result of this activity.

  9. Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis.

    PubMed

    Kitson, Matthew T; Sarrazin, Christoph; Toniutto, Pierluigi; Eslick, Guy D; Roberts, Stuart K

    2014-12-01

    The baseline 25-hydroxyvitamin D (25[OH]D) level has recently been reported to be an independent predictor of sustained virologic response (SVR) to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. However, studies have yielded inconsistent results. Thus, we conducted a systematic review and meta-analysis to clarify any association between baseline 25(OH)D level and SVR in HCV therapy. Two reviewers searched four electronic databases (Medline, Embase, PubMed, and Cochrane trials register) and relevant international conference proceedings up to March 2014 for studies treating chronic HCV infection with PEG-IFN plus RBV where baseline 25(OH)D level was tested. Studies involving patients with HIV co-infection, previous liver transplantation or those receiving vitamin D supplementation were excluded. The mean baseline 25(OH)D level was compared between those who achieved and those who failed to achieve SVR. Pooled standard difference in mean 25(OH)D level, odds ratios (OR) and 95% confidence intervals (CI) were calculated with the Comprehensive Meta-Analysis software (version 2.0) using a random effects model. 11 studies comprising 2605 patients were included in the meta-analysis. There was no significant association between the baseline mean 25(OH)D level and SVR (OR 1.44, 95% CI 0.92-2.26; p=0.11), either in patients infected with genotypes 1/4/5 (OR 1.48, 95% CI 0.94-2.34; p=0.09) or genotypes 2/3 (OR 1.51, 95% CI 0.26-8.87; p=0.65). The baseline 25(OH)D level is not associated with SVR to PEG-IFN plus RBV therapy in chronic HCV infection, regardless of genotype. Any effect of vitamin D supplementation on SVR is yet to be definitively determined. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  10. Exploring Adventure Therapy as an Early Intervention for Struggling Adolescents

    ERIC Educational Resources Information Center

    Dobud, Will

    2016-01-01

    This paper presents an account of a research project that explored the experiences of adolescents struggling with behavioral and emotional issues, who participated in a 14-day adventure therapy program in Australia referred to by the pseudonym, "Onward Adventures". All participants of this program over the age of 16 who completed within…

  11. Possible prevention of chronic hepatitis B by early interferon therapy.

    PubMed

    Trépo, C; Chemin, I; Petit, M A; Chossegros, P; Zoulim, F; Chevallier, P; Sepetjan, M

    1990-01-01

    A study is currently underway to investigate the efficacy of interferon therapy in patients with prolonged (greater than or equal to 10 weeks but less than 6 months) hepatitis B infection. To date, a total of 15 patients have been enrolled in the study and randomly assigned to receive either placebo for 24 weeks (n = 8) or interferon 5 million units subcutaneously 3 times a week for 24 weeks (n = 7), with follow up for 1 year. Thirteen patients have completed the follow-up period: seven patients in the placebo group and six in the treated group. Five of the six treated patients completely eradicated the infection during interferon therapy, with clearance of hepatitis B e and surface antigens, and seroconversion to antibody positivity in each case. Two of the eight placebo patients seroconverted during the placebo period. Clearance of hepatitis B e antigen was associated with a sudden rise in serum transaminase levels and an exacerbation of hepatitis, a phenomenon that has also been reported in chronic hepatitis B patients who have responded well to interferon therapy. Therapy was well tolerated in all cases. Our results suggest that interferon treatment of patients with prolonged hepatitis B infection may prevent progression to chronicity. If confirmed by further study, they should trigger more vigilant screening for patients with raised serum transaminase levels and viral markers of hepatitis B infection.

  12. Steroid plus antiviral treatment for Bell's palsy.

    PubMed

    Kang, H M; Jung, S Y; Byun, J Y; Park, M S; Yeo, S G

    2015-05-01

    The effectiveness of antiviral agents for the treatment of Bell's palsy is uncertain. We evaluated whether a steroid with an antiviral agent (S + A group) provided better recovery outcomes than a steroid alone (S group) in patients with Bell's palsy. A total of 1342 patients diagnosed with Bell's palsy who visited the Kyung Hee Medical Center in Seoul, Korea, from 2002 to 2012 were included in this study. Patients in the S + A group were treated with prednisolone and antiviral agents (n = 569) and those in the S group with prednisolone alone (n = 773). Outcomes were measured using the House-Brackmann (HB) scale according to age, initial disease severity, electroneurography (ENoG) findings and underlying comorbidities. The rate of recovery (HB grades I and II) with initially severe Bell's palsy (HB grades V and VI) was higher in the S + A than in the S group (P = 0.001). However, the rates of recovery were similar with initially moderate palsy (HB grades II-IV) (P = 0.502). In patients classified according to age and ENoG-determined severity of palsy, the overall recovery rate was higher in the S + A than in the S group, but the differences were not statistically significant (P > 0.05 for both). The recovery rate without diabetes mellitus (DM) and hypertension (HTN) was higher in the S + A group than in the S group (P = 0.031). But in the patients with HTN and DM, the difference in recovery rates between the S + A and S groups was not statistically significant (P = 0.805). Treatment with a steroid plus antiviral agent resulted in significantly higher recovery rates than steroid therapy alone in patients with initially severe Bell's palsy and without either HTN or DM, and a nonsignificant trend towards higher recovery rates in all patients with Bell's palsy in this study. Antiviral agents may therefore help in the treatment of Bell's palsy. © 2014 The Association for the Publication of the Journal of Internal Medicine.

  13. Implications of early and guideline adherent physical therapy for low back pain on utilization and costs.

    PubMed

    Childs, John D; Fritz, Julie M; Wu, Samuel S; Flynn, Timothy W; Wainner, Robert S; Robertson, Eric K; Kim, Forest S; George, Steven Z

    2015-04-09

    Initial management decisions following a new episode of low back pain (LBP) are thought to have profound implications for health care utilization and costs. The purpose of this study was to evaluate the impact of early and guideline adherent physical therapy for low back pain on utilization and costs within the Military Health System (MHS). Patients presenting to a primary care setting with a new complaint of LBP from January 1, 2007 to December 31, 2009 were identified from the MHS Management Analysis and Reporting Tool. Descriptive statistics, utilization, and costs were examined on the basis of timing of referral to physical therapy and adherence to practice guidelines over a 2-year period. Utilization outcomes (advanced imaging, lumbar injections or surgery, and opioid use) were compared using adjusted odds ratios with 99% confidence intervals. Total LBP-related health care costs over the 2-year follow-up were compared using linear regression models. 753,450 eligible patients with a primary care visit for LBP between 18-60 years of age were considered. Physical therapy was utilized by 16.3% (n = 122,723) of patients, with 24.0% (n = 17,175) of those receiving early physical therapy that was adherent to recommendations for active treatment. Early referral to guideline adherent physical therapy was associated with significantly lower utilization for all outcomes and 60% lower total LBP-related costs. The potential for cost savings in the MHS from early guideline adherent physical therapy may be substantial. These results also extend the findings from similar studies in civilian settings by demonstrating an association between early guideline adherent care and utilization and costs in a single payer health system. Future research is necessary to examine which patients with LBP benefit early physical therapy and determine strategies for providing early guideline adherent care.

  14. Analysis of inflammasomes and antiviral sensing components reveals decreased expression of NLRX1 in HIV-positive patients assuming efficient antiretroviral therapy.

    PubMed

    Nasi, Milena; De Biasi, Sara; Bianchini, Elena; Digaetano, Margherita; Pinti, Marcello; Gibellini, Lara; Pecorini, Simone; Carnevale, Gianluca; Guaraldi, Giovanni; Borghi, Vanni; Mussini, Cristina; Cossarizza, Andrea

    2015-09-24

    Few studies have investigated the importance of different components of the inflammasome system and of innate mitochondrial sensing (IMS) pathways in HIV infection and its treatment. We analysed the expression of several components of the inflammasome and of the IMS in HIV-positive patients taking successful combination antiretroviral therapy (cART). We enrolled 20 HIV-positive patients under cART, who achieved viral suppression since at least 10 months and 20 age and sex-matched healthy donors. By RT-PCR, using peripheral blood mononuclear cells (PBMCs), we quantified the mRNA expression of 16 genes involved in inflammasome activation and regulation (AIM2, NAIP, PYCARD, CASP1, CASP5, NLRP6, NLRP1, NLRP3, TXNIP, BCL2, NLRC4, PANX1, P2RX7, IL-18, IL-1β, SUGT1) and eight genes involved in IMS (MFN2, MFN1, cGAS, RIG-I, MAVS, NLRX1, RAB32, STING). Compared with controls, HIV-positive patients showed significantly lower mRNA levels of the mitochondrial protein NLRX1, which plays a key role in regulating apoptotic cell death; main PBMC subpopulations behave in a similar manner. No differences were observed in the expression of inflammasome components, which however showed complex correlations. The decreased level of NLRX1 in HIV infection could suggest that the virus is able to downregulate mechanisms linked to triggering of cell death in several immune cell types. The fact that HIV-positive patients did not show altered expression of inflammasome components, nor of most genes involved in IMS, suggests that the infection and/or the chronic immune activation does not influence the transcriptional machinery of innate mechanisms able to trigger inflammation at different levels.

  15. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection.

    PubMed

    Lundgren, Jens D; Babiker, Abdel G; Gordin, Fred; Emery, Sean; Grund, Birgit; Sharma, Shweta; Avihingsanon, Anchalee; Cooper, David A; Fätkenheuer, Gerd; Llibre, Josep M; Molina, Jean-Michel; Munderi, Paula; Schechter, Mauro; Wood, Robin; Klingman, Karin L; Collins, Simon; Lane, H Clifford; Phillips, Andrew N; Neaton, James D

    2015-08-27

    Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter. We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause. A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions. The initiation of

  16. The Underutilization of Occupational Therapy in Transdisciplinary Early Intervention Services

    ERIC Educational Resources Information Center

    Minard, Carey

    2018-01-01

    Early intervention (EI) services are mandated by Part C of The Individuals with Disabilities Education Act (IDEA, 2004). The EI team, a multidisciplinary team overseen by individual states, is charged with providing family-centered services to support child development in the natural environment. This article examines the use of occupational…

  17. Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR.

    PubMed

    Thompson, Alexander J; Santoro, Rosanna; Piazzolla, Valeria; Clark, Paul J; Naggie, Susanna; Tillmann, Hans L; Patel, Keyur; Muir, Andrew J; Shianna, Kevin V; Mottola, Leonardo; Petruzzellis, Daniela; Romano, Mario; Sogari, Fernando; Facciorusso, Domenico; Goldstein, David B; McHutchison, John G; Mangia, Alessandra

    2011-02-01

    Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10(-6) for rs1127354 and P = 10(-7) for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10(-11) ). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08-0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR. Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose

  18. Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

    PubMed

    Gagyor, Ildiko; Madhok, Vishnu B; Daly, Fergus; Somasundara, Dhruvashree; Sullivan, Michael; Gammie, Fiona; Sullivan, Frank

    2015-11-09

    Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. This review was first published in 2001 and revised several times, most recently in 2009. This version replaces an update of the review in Issue 7 of the Cochrane Library subsequently withdrawn because of an ongoing investigation into the reliability of data from an included study. To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains. Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. Ten trials, including 2280 participants, met the inclusion criteria and are included in the final analysis. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recoveryWe found a significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.39 to 0.97, n = 1315). For people with severe Bell

  19. Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

    PubMed

    Gagyor, Ildiko; Madhok, Vishnu B; Daly, Fergus; Somasundara, Dhruvashree; Sullivan, Michael; Gammie, Fiona; Sullivan, Frank

    2015-07-01

    Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains. Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. Eleven trials, including 2883 participants, met the inclusion criteria and are included in the final analysis. We added four studies to the previous review for this update. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recoveryWe found no significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.47 to 1.02, n = 1715). For people with severe Bell's palsy (House-Brackmann scores of 5 and 6 or the equivalent in other scales), we found a reduction in the rate of incomplete recovery at month six when antivirals plus corticosteroids were used (RR 0.64, 95% CI 0.41 to 0

  20. The growth and potential of human antiviral monoclonal antibody therapeutics.

    PubMed

    Marasco, Wayne A; Sui, Jianhua

    2007-12-01

    Monoclonal antibodies (mAbs) have long provided powerful research tools for virologists to understand the mechanisms of virus entry into host cells and of antiviral immunity. Even so, commercial development of human (or humanized) mAbs for the prophylaxis, preemptive and acute treatment of viral infections has been slow. This is surprising, as new antibody discovery tools have increased the speed and precision with which potent neutralizing human antiviral mAbs can be identified. As longstanding barriers to antiviral mAb development, such as antigenic variability of circulating viral strains and the ability of viruses to undergo neutralization escape, are being overcome, deeper insight into the mechanisms of mAb action and engineering of effector functions are also improving the efficacy of antiviral mAbs. These successes, in both industrial and academic laboratories, coupled with ongoing changes in the biomedical and regulatory environments, herald an era when the commercial development of human antiviral mAb therapies will likely surge.

  1. Predicting Retrograde Autobiographical Memory Changes Following Electroconvulsive Therapy: Relationships between Individual, Treatment, and Early Clinical Factors.

    PubMed

    Martin, Donel M; Gálvez, Verònica; Loo, Colleen K

    2015-06-19

    Loss of personal memories experienced prior to receiving electroconvulsive therapy is common and distressing and in some patients can persist for many months following treatment. Improved understanding of the relationships between individual patient factors, electroconvulsive therapy treatment factors, and clinical indicators measured early in the electroconvulsive therapy course may help clinicians minimize these side effects through better management of the electroconvulsive therapy treatment approach. In this study we examined the associations between the above factors for predicting retrograde autobiographical memory changes following electroconvulsive therapy. Seventy-four depressed participants with major depressive disorder were administered electroconvulsive therapy 3 times per week using either a right unilateral or bitemporal electrode placement and brief or ultrabrief pulse width. Verbal fluency and retrograde autobiographical memory (assessed using the Columbia Autobiographical Memory Interview - Short Form) were tested at baseline and after the last electroconvulsive therapy treatment. Time to reorientation was measured immediately following the third and sixth electroconvulsive therapy treatments. Results confirmed the utility of measuring time to reorientation early during the electroconvulsive therapy treatment course as a predictor of greater retrograde amnesia and the importance of assessing baseline cognitive status for identifying patients at greater risk for developing later side effects. With increased number of electroconvulsive therapy treatments, older age was associated with increased time to reorientation. Consistency of verbal fluency performance was moderately correlated with change in Columbia Autobiographical Memory Interview - Short Form scores following right unilateral electroconvulsive therapy. Electroconvulsive therapy treatment techniques associated with lesser cognitive side effects should be particularly considered for

  2. Predicting Retrograde Autobiographical Memory Changes Following Electroconvulsive Therapy: Relationships between Individual, Treatment, and Early Clinical Factors

    PubMed Central

    Gálvez, Verònica; Loo, Colleen K.

    2015-01-01

    Background: Loss of personal memories experienced prior to receiving electroconvulsive therapy is common and distressing and in some patients can persist for many months following treatment. Improved understanding of the relationships between individual patient factors, electroconvulsive therapy treatment factors, and clinical indicators measured early in the electroconvulsive therapy course may help clinicians minimize these side effects through better management of the electroconvulsive therapy treatment approach. In this study we examined the associations between the above factors for predicting retrograde autobiographical memory changes following electroconvulsive therapy. Methods: Seventy-four depressed participants with major depressive disorder were administered electroconvulsive therapy 3 times per week using either a right unilateral or bitemporal electrode placement and brief or ultrabrief pulse width. Verbal fluency and retrograde autobiographical memory (assessed using the Columbia Autobiographical Memory Interview – Short Form) were tested at baseline and after the last electroconvulsive therapy treatment. Time to reorientation was measured immediately following the third and sixth electroconvulsive therapy treatments. Results: Results confirmed the utility of measuring time to reorientation early during the electroconvulsive therapy treatment course as a predictor of greater retrograde amnesia and the importance of assessing baseline cognitive status for identifying patients at greater risk for developing later side effects. With increased number of electroconvulsive therapy treatments, older age was associated with increased time to reorientation. Consistency of verbal fluency performance was moderately correlated with change in Columbia Autobiographical Memory Interview – Short Form scores following right unilateral electroconvulsive therapy. Conclusions: Electroconvulsive therapy treatment techniques associated with lesser cognitive side

  3. Antiviral agents for infectious mononucleosis (glandular fever).

    PubMed

    De Paor, Muireann; O'Brien, Kirsty; Fahey, Tom; Smith, Susan M

    2016-12-08

    Infectious mononucleosis (IM) is a clinical syndrome, usually caused by the Epstein Barr virus (EPV), characterised by lymphadenopathy, fever and sore throat. Most cases of symptomatic IM occur in older teenagers or young adults. Usually IM is a benign self-limiting illness and requires only symptomatic treatment. However, occasionally the disease course can be complicated or prolonged and lead to decreased productivity in terms of school or work. Antiviral medications have been used to treat IM, but the use of antivirals for IM is controversial. They may be effective by preventing viral replication which helps to keep the virus inactive. However, there are no guidelines for antivirals in IM. To assess the effects of antiviral therapy for infectious mononucleosis (IM). We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, March 2016), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1946 to 15 April 2016), Embase (1974 to 15 April 2016), CINAHL (1981 to 15 April 2016), LILACS (1982 to 15 April 2016) and Web of Science (1955 to 15 April 2016). We searched the World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov for completed and ongoing trials. We included randomised controlled trials (RCTs) comparing antivirals versus placebo or no treatment in IM. We included trials of immunocompetent participants of any age or sex with clinical and laboratory-confirmed diagnosis of IM, who had symptoms for up to 14 days. Our primary outcomes were time to clinical recovery and adverse events and side effects of medication. Secondary outcomes included duration of abnormal clinical examination, complications, viral shedding, health-related quality of life, days missing from school or work and economic outcomes. Two review authors independently assessed studies for inclusion, assessed the included studies' risk of bias and extracted data using a

  4. Cognitive Development in Infantile-Onset Pompe Disease Under Very Early Enzyme Replacement Therapy.

    PubMed

    Lai, Chih-Jou; Hsu, Ting-Rong; Yang, Chia-Feng; Chen, Shyi-Jou; Chuang, Ya-Chin; Niu, Dau-Ming

    2016-12-01

    Most patients with infantile-onset Pompe disease die in early infancy before beginning enzyme replacement therapy, which has made it difficult to evaluate the impact of Pompe disease on cognitive development. Patients with infantile-onset Pompe disease can survive with enzyme replacement therapy, and physicians can evaluate cognitive development in these patients. We established an effective newborn screening program with quick clinical diagnostic criteria. Cognitive and motor development were evaluated using the Bayley Scales of Infant and Toddler Development-Third Edition at 6, 12, and 24 months of age. The patients who were treated very early demonstrate normal cognitive development with no significant change in cognition during this period (P = .18 > .05). The cognitive development was positively correlated with motor development (r = 0.533, P = .011). The results indicated that very early enzyme replacement therapy could protect cognitive development in patients with infantile-onset Pompe disease up to 24 months of age. © The Author(s) 2016.

  5. Viral ancestors of antiviral systems.

    PubMed

    Villarreal, Luis P

    2011-10-01

    All life must survive their corresponding viruses. Thus antiviral systems are essential in all living organisms. Remnants of virus derived information are also found in all life forms but have historically been considered mostly as junk DNA. However, such virus derived information can strongly affect host susceptibility to viruses. In this review, I evaluate the role viruses have had in the origin and evolution of host antiviral systems. From Archaea through bacteria and from simple to complex eukaryotes I trace the viral components that became essential elements of antiviral immunity. I conclude with a reexamination of the 'Big Bang' theory for the emergence of the adaptive immune system in vertebrates by horizontal transfer and note how viruses could have and did provide crucial and coordinated features.

  6. Viral Ancestors of Antiviral Systems

    PubMed Central

    Villarreal, Luis P.

    2011-01-01

    All life must survive their corresponding viruses. Thus antiviral systems are essential in all living organisms. Remnants of virus derived information are also found in all life forms but have historically been considered mostly as junk DNA. However, such virus derived information can strongly affect host susceptibility to viruses. In this review, I evaluate the role viruses have had in the origin and evolution of host antiviral systems. From Archaea through bacteria and from simple to complex eukaryotes I trace the viral components that became essential elements of antiviral immunity. I conclude with a reexamination of the ‘Big Bang’ theory for the emergence of the adaptive immune system in vertebrates by horizontal transfer and note how viruses could have and did provide crucial and coordinated features. PMID:22069523

  7. Early Intervention and Nonpharmacological Therapy of Myopia in Young Adults

    PubMed Central

    Gładysiak, Aleksandra; Ślęzak, Daniel

    2018-01-01

    Myopia is a condition of the eye where parallel rays focus in front of, instead of on, the retina, which results in excessive refractive power of the cornea or the lens or eyeball elongation. Studies carried out in recent years show that the etiology of myopia is complex with genetic and environmental factors playing a role. Refraction defects decrease the quality of vision, while progressing myopia can lead to partial loss of vision, which can be particularly dramatic in young adults. Therefore, it is so crucial to take appropriate actions aimed at preventing myopia progression. This is a review of nonpharmacological therapeutic possibilities of refraction defect prevention in young adults, with special regard to myofascial therapy, osteopathy, and massage of acupuncture points surrounding the eye. PMID:29576878

  8. TRIM25 in the Regulation of the Antiviral Innate Immunity.

    PubMed

    Martín-Vicente, María; Medrano, Luz M; Resino, Salvador; García-Sastre, Adolfo; Martínez, Isidoro

    2017-01-01

    TRIM25 is an E3 ubiquitin ligase enzyme that is involved in various cellular processes, including regulation of the innate immune response against viruses. TRIM25-mediated ubiquitination of the cytosolic pattern recognition receptor RIG-I is an essential step for initiation of the intracellular antiviral response and has been thoroughly documented. In recent years, however, additional roles of TRIM25 in early innate immunity are emerging, including negative regulation of RIG-I, activation of the melanoma differentiation-associated protein 5-mitochondrial antiviral signaling protein-TRAF6 antiviral axis and modulation of p53 levels and activity. In addition, the ability of TRIM25 to bind RNA may uncover new mechanisms by which this molecule regulates intracellular signaling and/or RNA virus replication.

  9. TRIM25 in the Regulation of the Antiviral Innate Immunity

    PubMed Central

    Martín-Vicente, María; Medrano, Luz M.; Resino, Salvador; García-Sastre, Adolfo; Martínez, Isidoro

    2017-01-01

    TRIM25 is an E3 ubiquitin ligase enzyme that is involved in various cellular processes, including regulation of the innate immune response against viruses. TRIM25-mediated ubiquitination of the cytosolic pattern recognition receptor RIG-I is an essential step for initiation of the intracellular antiviral response and has been thoroughly documented. In recent years, however, additional roles of TRIM25 in early innate immunity are emerging, including negative regulation of RIG-I, activation of the melanoma differentiation-associated protein 5–mitochondrial antiviral signaling protein–TRAF6 antiviral axis and modulation of p53 levels and activity. In addition, the ability of TRIM25 to bind RNA may uncover new mechanisms by which this molecule regulates intracellular signaling and/or RNA virus replication. PMID:29018447

  10. The Antiviral Effect of Baicalin on Enterovirus 71 In Vitro

    PubMed Central

    Li, Xiang; Liu, Yuanyuan; Wu, Tingting; Jin, Yue; Cheng, Jianpin; Wan, Changbiao; Qian, Weihe; Xing, Fei; Shi, Weifeng

    2015-01-01

    Baicalin is a flavonoid compound extracted from Scutellaria roots that has been reported to possess antibacterial, anti-inflammatory, and antiviral activities. However, the antiviral effect of baicalin on enterovirus 71 (EV71) is still unknown. In this study, we found that baicalin showed inhibitory activity on EV71 infection and was independent of direct virucidal or prophylactic effect and inhibitory viral absorption. The expressions of EV71/3D mRNA and polymerase were significantly blocked by baicalin treatment at early stages of EV71 infection. In addition, baicalin could decrease the expressions of FasL and caspase-3, as well as inhibit the apoptosis of EV71-infected human embryonal rhabdomyosarcoma (RD) cells. Altogether, these results indicate that baicalin exhibits potent antiviral effect on EV71 infection, probably through inhibiting EV71/3D polymerase expression and Fas/FasL signaling pathways. PMID:26295407

  11. The Impact of Radiation Oncologists on the Early Adoption of Hypofractionated Radiation Therapy for Early-Stage Breast Cancer.

    PubMed

    Boero, Isabel J; Gillespie, Erin F; Hou, Jiayi; Paravati, Anthony J; Kim, Ellen; Einck, John P; Yashar, Catheryn; Mell, Loren K; Murphy, James D

    2017-03-01

    Despite multiple randomized trials showing the efficacy of hypofractionated radiation therapy in early-stage breast cancer, the United States has been slow to adopt this treatment. The goal of this study was to evaluate the impact of individual radiation oncologists on the early adoption of hypofractionated radiation therapy for early-stage breast cancer. We identified 22,233 Medicare beneficiaries with localized breast cancer that was diagnosed from 2004 to 2011 who underwent breast-conserving surgery with adjuvant radiation. Multilevel, multivariable logistic models clustered by radiation oncologist and geographic practice area were used to determine the impact of the provider and geographic region on the likelihood of receiving hypofractionated compared with standard fractionated radiation therapy while controlling for a patient's clinical and demographic covariates. Odds ratios (OR) describe the impact of demographic or clinical covariates, and the median OR (MOR) describes the relative impact of the individual radiation oncologist and geographic region on the likelihood of undergoing hypofractionated radiation therapy. Among the entire cohort, 2333 women (10.4%) were treated with hypofractionated radiation therapy, with unadjusted rates ranging from 0.0% in the bottom quintile of radiation oncologists to 30.4% in the top quintile. Multivariable analysis found that the individual radiation oncologist (MOR 3.08) had a greater impact on the use of hypofractionation than did geographic region (MOR 2.10) or clinical and demographic variables. The impact of the provider increased from the year 2004 to 2005 (MOR 2.82) to the year 2010 to 2011 (MOR 3.16) despite the publication of long-term randomized trial results in early 2010. Male physician and radiation oncologists treating the highest volume of breast cancer patients were less likely to perform hypofractionation (P<.05). The individual radiation oncologist strongly influenced the likelihood of a patient

  12. Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial

    PubMed Central

    Brummel, N.E.; Girard, T.D.; Ely, E.W.; Pandharipande, P.P.; Morandi, A.; Hughes, C.G.; Graves, A.J.; Shintani, A.K.; Murphy, E.; Work, B.; Pun, B.T.; Boehm, L.; Gill, T.M.; Dittus, R.S.; Jackson, J.C.

    2013-01-01

    PURPOSE Cognitive impairment after critical illness is common and debilitating. We developed a cognitive therapy program for critically ill patients and assessed the feasibility and safety of administering combined cognitive and physical therapy early during a critical illness. METHODS We randomized 87 medical and surgical ICU patients with respiratory failure and/or shock in a 1:1:2 manner to three groups: usual care, early once-daily physical therapy, or early once-daily physical therapy plus a novel, progressive, twice-daily cognitive therapy protocol. Cognitive therapy included orientation, memory, attention, and problem solving exercises, and other activities. We assessed feasibility outcomes of the early cognitive plus physical therapy intervention. At 3-months, we also assessed cognitive, functional and health-related quality of life outcomes. Data are presented as median [interquartile range] or frequency (%). RESULTS Early cognitive therapy was a delivered to 41/43 (95%) of cognitive plus physical therapy patients on 100% [92–100%] of study days beginning 1.0 [1.0–1.0] day following enrollment. Physical therapy was received by 17/22 (77%) of usual care patients, by 21/22 (95%) of physical therapy only patients and 42/43 (98%) of cognitive plus physical therapy patients on 17% [10–26%], 67% [46–87%] and 75% [59–88%] of study days, respectively. Cognitive, functional and health-related quality of life outcomes did not differ between groups at 3-month follow-up. CONCLUSIONS This pilot study demonstrates that early rehabilitation can be extended beyond physical therapy to include cognitive therapy. Future work to determine optimal patient selection, intensity of treatment and benefits of cognitive therapy in the critically ill is needed. PMID:24257969

  13. Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial.

    PubMed

    Brummel, N E; Girard, T D; Ely, E W; Pandharipande, P P; Morandi, A; Hughes, C G; Graves, A J; Shintani, A; Murphy, E; Work, B; Pun, B T; Boehm, L; Gill, T M; Dittus, R S; Jackson, J C

    2014-03-01

    Cognitive impairment after critical illness is common and debilitating. We developed a cognitive therapy program for critically ill patients and assessed the feasibility and safety of administering combined cognitive and physical therapy early during a critical illness. We randomized 87 medical and surgical ICU patients with respiratory failure and/or shock in a 1:1:2 manner to three groups: usual care, early once-daily physical therapy, or early once-daily physical therapy plus a novel, progressive, twice-daily cognitive therapy protocol. Cognitive therapy included orientation, memory, attention, and problem-solving exercises, and other activities. We assessed feasibility outcomes of the early cognitive plus physical therapy intervention. At 3 months, we also assessed cognitive, functional, and health-related quality of life outcomes. Data are presented as median (interquartile range) or frequency (%). Early cognitive therapy was a delivered to 41/43 (95%) of cognitive plus physical therapy patients on 100% (92-100%) of study days beginning 1.0 (1.0-1.0) day following enrollment. Physical therapy was received by 17/22 (77%) of usual care patients, by 21/22 (95%) of physical therapy only patients, and 42/43 (98%) of cognitive plus physical therapy patients on 17% (10-26%), 67% (46-87%), and 75% (59-88%) of study days, respectively. Cognitive, functional, and health-related quality of life outcomes did not differ between groups at 3-month follow-up. This pilot study demonstrates that early rehabilitation can be extended beyond physical therapy to include cognitive therapy. Future work to determine optimal patient selection, intensity of treatment, and benefits of cognitive therapy in the critically ill is needed.

  14. Early cessation of pressure garment therapy results in scar contraction and thickening

    PubMed Central

    DeBruler, Danielle M.; Zbinden, Jacob C.; Baumann, Molly E.; Blackstone, Britani N.; Malara, Megan M.; Bailey, J. Kevin

    2018-01-01

    Pressure garment therapy is often prescribed to improve scar properties following full-thickness burn injuries. Pressure garment therapy is generally recommended for long periods of time following injury (1–2 years), though it is plagued by extremely low patient compliance. The goal of this study was to examine the effects of early cessation of pressure garment therapy on scar properties. Full-thickness burn injuries were created along the dorsum of red Duroc pigs. The burn eschar was excised and wound sites autografted with split-thickness skin. Scars were treated with pressure garments within 1 week of injury and pressure was maintained for either 29 weeks (continuous pressure) or for 17 weeks followed by cessation of pressure for an additional 12 weeks (pressure released); scars receiving no treatment served as controls. Scars that underwent pressure garment therapy were significantly smoother and less contracted with decreased scar height compared to control scars at 17 weeks. These benefits were maintained in the continuous pressure group until week 29. In the pressure released group, grafts significantly contracted and became more raised, harder and rougher after the therapy was discontinued. Pressure cessation also resulted in large changes in collagen fiber orientation and increases in collagen fiber thickness. The results suggest that pressure garment therapy effectively improves scar properties following severe burn injury; however, early cessation of the therapy results in substantial loss of these improvements. PMID:29897933

  15. Early cessation of pressure garment therapy results in scar contraction and thickening.

    PubMed

    DeBruler, Danielle M; Zbinden, Jacob C; Baumann, Molly E; Blackstone, Britani N; Malara, Megan M; Bailey, J Kevin; Supp, Dorothy M; Powell, Heather M

    2018-01-01

    Pressure garment therapy is often prescribed to improve scar properties following full-thickness burn injuries. Pressure garment therapy is generally recommended for long periods of time following injury (1-2 years), though it is plagued by extremely low patient compliance. The goal of this study was to examine the effects of early cessation of pressure garment therapy on scar properties. Full-thickness burn injuries were created along the dorsum of red Duroc pigs. The burn eschar was excised and wound sites autografted with split-thickness skin. Scars were treated with pressure garments within 1 week of injury and pressure was maintained for either 29 weeks (continuous pressure) or for 17 weeks followed by cessation of pressure for an additional 12 weeks (pressure released); scars receiving no treatment served as controls. Scars that underwent pressure garment therapy were significantly smoother and less contracted with decreased scar height compared to control scars at 17 weeks. These benefits were maintained in the continuous pressure group until week 29. In the pressure released group, grafts significantly contracted and became more raised, harder and rougher after the therapy was discontinued. Pressure cessation also resulted in large changes in collagen fiber orientation and increases in collagen fiber thickness. The results suggest that pressure garment therapy effectively improves scar properties following severe burn injury; however, early cessation of the therapy results in substantial loss of these improvements.

  16. Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus: A Review of Cases Reported to the U.S. Food and Drug Administration Adverse Event Reporting System.

    PubMed

    Bersoff-Matcha, Susan J; Cao, Kelly; Jason, Mihaela; Ajao, Adebola; Jones, S Christopher; Meyer, Tamra; Brinker, Allen

    2017-06-06

    Direct-acting antiviral agents (DAAs) are used increasingly to treat hepatitis C virus (HCV) infection. Reports were published recently on hepatitis B virus (HBV) reactivation (HBV-R) in patients with HBV-HCV co-infection. Hepatitis B virus reactivation, defined as an abrupt increase in HBV replication in patients with inactive or resolved HBV infection, may result in clinically significant hepatitis. To assess whether HBV-R is a safety concern in patients receiving HCV DAAs. Descriptive case series. U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). 29 patients with HBV-R receiving HCV DAAs. Clinical and laboratory data. The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom HBV-R developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others. The quality of information varied among reports. Because reporting is voluntary, HBV-R associated with DAAs likely is underreported. Hepatitis B virus reactivation is a newly identified safety concern in patients with HBV-HCV co-infection treated with DAAs. Patients with a history of HBV require clinical monitoring while receiving DAA therapy. Studies would help determine the risk factors for HBV-R, define monitoring frequency, and identify patients who may benefit from HBV prophylaxis and treatment. DAAs remain a safe and highly effective treatment for the

  17. Transdermal Nitroglycerin Therapy May Not Prevent Early Postmenopausal Bone Loss

    PubMed Central

    Wimalawansa, Sunil J.; Grimes, Julia P.; Wilson, Alan C.; Hoover, Donald R.

    2009-01-01

    Context: Osteoporosis is common among postmenopausal women; animal studies and human pilot studies support the concept of nitric oxide (NO) donors reducing bone mineral density loss. Objective: The objective of the study was to evaluate whether NO donor, nitroglycerin, prevents postmenopausal bone loss. Design: This was a 3-yr randomized, double blinded, single-center, placebo-controlled clinical trial. Setting: The single-center study was conducted at the University of Medicine and Dentistry-Robert Wood Johnson Medical School (New Brunswick, NJ). Participants: Participants included 186 postmenopausal women aged 40–65 yr, with lumbar bone mineral density (BMD) T-scores of 0 to −2.5. Intervention: Women, stratified by lumbar T-score (<−1.50 and ≥−1.50) and years since menopause (≤5 and >5 yr), were randomized to receive nitroglycerin ointment (22.5 mg as Nitro-Bid) or placebo ointment received daily for 3 yr. Both groups took 630 mg daily calcium plus 400 IU vitamin D supplements. Measurements: BMD was measured at 6 months and annually by dual-energy x-ray absorptiometry. Percent change in lumbar vertebrae BMD was the primary outcome. Hip BMD, total body bone mineral content, and height were secondary outcomes. Results: After 36 months of therapy, changes of −2.1% in the active group (n = 88) and −2.5% in the placebo group (n = 82) in lumbar spine BMD were seen (P = 0.59; 95% confidence interval −1.001, 1.975). Secondary outcomes also did not differ by intervention arm. The active group reported more headaches compared with the placebo group (57 vs. 14%, P < 0.001). Other adverse and serious adverse events were not different. Conclusions: BMD changes did not substantially differ between postmenopausal women who received the dose of nitroglycerin tested, in comparison with a placebo. Once-daily dosing with 22.5 mg of transdermal-administered nitroglycerin was not effective (compliance adjusted dose was only ∼16 mg/d); a sub-therapeutic dose. PMID

  18. Role of chemotherapy and targeted therapy in early-stage non-small cell lung cancer.

    PubMed

    Nagasaka, Misako; Gadgeel, Shirish M

    2018-01-01

    Adjuvant platinum based chemotherapy is accepted as standard of care in stage II and III non-small cell lung cancer (NSCLC) patients and is often considered in patients with stage IB disease who have tumors ≥ 4 cm. The survival advantage is modest with approximately 5% at 5 years. Areas covered: This review article presents relevant data regarding chemotherapy use in the perioperative setting for early stage NSCLC. A literature search was performed utilizing PubMed as well as clinical trial.gov. Randomized phase III studies in this setting including adjuvant and neoadjuvant use of chemotherapy as well as ongoing trials on targeted therapy and immunotherapy are also discussed. Expert commentary: With increasing utilization of screening computed tomography scans, it is possible that the percentage of early stage NSCLC patients will increase in the coming years. Benefits of adjuvant chemotherapy in early stage NSCLC patients remain modest. There is a need to better define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy. Trials for adjuvant targeted therapy, including adjuvant EGFR-TKI trials and trials of immunotherapy drugs are ongoing and will define the role of these agents as adjuvant therapy.

  19. Prolonged Exposure Therapy for a Vietnam Veteran with PTSD and Early-Stage Dementia

    ERIC Educational Resources Information Center

    Duax, Jeanne M.; Waldron-Perrine, Brigid; Rauch, Sheila A. M.; Adams, Kenneth M.

    2013-01-01

    Although prolonged exposure therapy (PE) is considered an evidence-based treatment for PTSD, there has been little published about the use of this treatment for older adults with comorbid early-stage dementia. As the number of older adults in the United States continues to grow, so will their unique mental health needs. The present article…

  20. Photodynamic therapy of early stage cancer of lung, esophagus, and stomach with two different photosensitizers

    NASA Astrophysics Data System (ADS)

    Chissov, Valery I.; Sokolov, Victor V.; Trakhtenberg, A. K.; Mamontov, A. S.; Vaschakmadze, L. A.; Frank, George A.; Filonenko, E. V.; Telegina, L. V.; Belous, T. A.; Gladunov, V. K.; Aristarkhova, E. I.; Zharkova, Natalia N.; Menenkov, V. D.

    1996-01-01

    The paper presents the results of photodynamic therapy (PDT) of early-stage cancer of lung (17 patients), esophagus (8 patients) and stomach (10 patients). Fifteen patients had second primary tumors. New drugs photoheme and photosens were used as photosensitizers. Complete remission was obtained in 87%. The patients are followed up without relapses to 2.5 years.

  1. Efficacy of early physical therapy in severe Bell's palsy: a randomized controlled trial.

    PubMed

    Nicastri, Maria; Mancini, Patrizia; De Seta, Daniele; Bertoli, Gianantonio; Prosperini, Luca; Toni, Danilo; Inghilleri, Maurizio; Filipo, Roberto

    2013-01-01

    Bell's palsy (BP) is the most frequent form of peripheral palsy of the facial nerve. Prognosis for recovery is good for most patients; in the remaining cases, different grades of residual impairment persist. Physical therapy, in association with drug administration, aims to improve outcomes. To assess the efficacy of early physical therapy in association with standard drug administration versus pharmacological therapy only, in terms of time to maximum gains and grade of recovery of function, and to examine who will most benefit from rehabilitation. From June 2008 to May 2010, 232 individuals were evaluated. The 87 patients meeting the eligibility criteria were randomly assigned to the experimental group (prednisone and valacyclovir plus physical therapy, n = 39) or the control group (pharmacological therapy, n = 48) within 10 days of onset. Intention-to-treat analyses were done. The physical therapy had a significant effect on grade (P = .038) and time (P = .044) to recovery only in patients presenting with severe facial palsy (House-Brackmann [HB] grade V/VI). No significant differences were found between the study and control groups for outcome of synkinesis. Physical therapy appears to be effective only in the more severe BP (baseline HB grade V/VI), whereas less severe BP (baseline HB grade IV) results in complete spontaneous recovery, regardless of physical therapy.

  2. Music therapy for early cognitive rehabilitation post-childhood TBI: an intrinsic mixed methods case study.

    PubMed

    Bower, Janeen; Catroppa, Cathy; Grocke, Denise; Shoemark, Helen

    2014-10-01

    The primary aim of this case study was to explore the behavioural changes of a paediatric patient in post-traumatic amnesia (PTA) during a music therapy session. A secondary objective was to measure the effect of the music therapy intervention on agitation. Video data from pre, during and post-music therapy sessions were collected and analysed using video micro-analysis and the Agitated Behaviour Scale. The participant displayed four discrete categories of behaviours: Neutral, Acceptance, Recruitment and Rejection. Further analysis revealed brief but consistent and repeated periods of awareness and responsiveness to the live singing of familiar songs, which were classified as Islands of Awareness. Song offered an Environment of Potential to maximise these periods of emerging consciousness. The quantitative data analysis yielded inconclusive results in determining if music therapy was effective in reducing agitation during and immediately post the music therapy sessions. The process of micro-analysis illuminated four discrete participant behaviours not apparent in the immediate clinical setting. The results of this case suggest that the use of familiar song as a music therapy intervention may harness early patient responsiveness to foster cognitive rehabilitation in the early acute phase post-TBI.

  3. Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer.

    PubMed

    Blok, Erik J; Kroep, Judith R; Meershoek-Klein Kranenbarg, Elma; Duijm-de Carpentier, Marjolijn; Putter, Hein; Liefers, Gerrit-Jan; Nortier, Johan W R; Rutgers, Emiel J Th; Seynaeve, Caroline M; van de Velde, Cornelis J H

    2018-04-01

    For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47-0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38-0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13-1.06), although this additional analysis was underpowered for definite conclusions. This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

  4. Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy

    PubMed Central

    Engel, Jerome; McDermott, Michael P.; Wiebe, Samuel; Langfitt, John T.; Stern, John M.; Dewar, Sandra; Sperling, Michael R.; Gardiner, Irenita; Erba, Giuseppe; Fried, Itzhak; Jacobs, Margaret; Vinters, Harry V.; Mintzer, Scott; Kieburtz, Karl

    2016-01-01

    Context Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death. Objective We sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL). Design, Setting, and Participants The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged ≥ 12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003–2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual. Intervention Receipt of continued AED treatment (n=23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery. Main Outcome Measures The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation. Results Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio=∞; 95% CI, 11.8 to ∞;P <.001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was

  5. Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy

    PubMed Central

    Feng, Li Rebekah; Wolff, Brian S.; Lukkahatai, Nada; Espina, Alexandra; Saligan, Leorey N.

    2016-01-01

    Background Fatigue is one of the most debilitating side effects of cancer therapy. Identifying biomarkers early during cancer therapy may help us understand the biologic underpinnings of the persistence of fatigue following therapy. Objective We aimed to identify early biomarkers of fatigue by examining correlations of levels of cytokines during external beam radiation therapy (EBRT) with persistence of fatigue one year following treatment completion in men with non-metastatic prostate cancer (NM-PC). Methods A sample of 34 men with NM-PC scheduled to receive EBRT were followed at baseline (T1), midpoint of EBRT (T2), and one year following EBRT (T3). Demographic and clinical data were obtained by chart review. The Functional Assessment of Cancer Therapy-Fatigue (FACT-F) was administered to measure fatigue levels. Plasma cytokine levels were determined at T1 and T2 using the Bio-Rad Bio-Plex Cytokine Assay Kits. Results Significant correlations were observed between levels of IL-3, IL-8, IL-9, IL-10, IL-16, IP10, IFNα2, IFNγ, and SDF1α at T2 with worsening of fatigue from T1 to T3. Conclusions Immunological changes prior to chronic fatigue development may reflect the long term response to radiation therapy-induced damage. Implications for Practice Early biomarkers for chronic fatigue related to cancer therapy will help advance our understanding of the etiology of this distressing symptom and will help nurses identify patients at risk for developing chronic fatigue after cancer treatment. This information will also aide in patient education, as well as symptom management. PMID:27105468

  6. Effects of Cognitive Enhancement Therapy on Employment Outcomes in Early Schizophrenia: Results from a 2-Year Randomized Trial

    ERIC Educational Resources Information Center

    Eack, Shaun M.; Hogarty, Gerard E.; Greenwald, Deborah P.; Hogarty, Susan S.; Keshavan, Matcheri S.

    2011-01-01

    Objective: To examine the effects of psychosocial cognitive rehabilitation on employment outcomes in a randomized controlled trial for individuals with early course schizophrenia. Method: Early course schizophrenia outpatients (N = 58) were randomly assigned to cognitive enhancement therapy (CET) or an enriched supportive therapy (EST) control and…

  7. Multicenter randomized controlled trial comparing early versus late aquatic therapy after total hip or knee arthroplasty.

    PubMed

    Liebs, Thoralf R; Herzberg, Wolfgang; Rüther, Wolfgang; Haasters, Jörg; Russlies, Martin; Hassenpflug, Joachim

    2012-02-01

    To evaluate if the timing of aquatic therapy influences clinical outcomes after total knee arthroplasty (TKA) or total hip arthroplasty (THA). Multicenter randomized controlled trial with 3-, 6-, 12-, and 24-month follow-up. Two university hospitals, 1 municipal hospital, and 1 rural hospital. Patients (N=465) undergoing primary THA (n=280) or TKA (n=185): 156 men, 309 women. Patients were randomly assigned to receive aquatic therapy (pool exercises aimed at training of proprioception, coordination, and strengthening) after 6 versus 14 days after THA or TKA. Primary outcome was self-reported physical function as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 3-, 6-, 12-, and 24-months postoperatively. Results were compared with published thresholds for minimal clinically important improvements. Secondary outcomes included the Medical Outcomes Study 36-Item Short-Form Health Survey, Lequesne-Hip/Knee-Score, WOMAC-pain and stiffness scores, and patient satisfaction. Baseline characteristics of the 2 groups were similar. Analyzing the total study population did not result in statistically significant differences at all follow-ups. However, when performing subanalysis for THA and TKA, opposite effects of early aquatic therapy were seen between TKA and THA. After TKA all WOMAC subscales were superior in the early aquatic therapy group, with effect sizes of WOMAC physical function ranging from .22 to .39. After THA, however, all outcomes were superior in the late aquatic therapy group, with WOMAC effect sizes ranging from .01 to .19. However, the differences between treatment groups of these subanalyses were not statistically significant. Early start of aquatic therapy had contrary effects after TKA when compared with THA and it influenced clinical outcomes after TKA. Although the treatment differences did not achieve statistically significance, the effect size for early aquatic therapy after TKA had the same magnitude as the

  8. Early Change in Stroke Size Performs Best in Predicting Response to Therapy.

    PubMed

    Simpkins, Alexis Nétis; Dias, Christian; Norato, Gina; Kim, Eunhee; Leigh, Richard

    2017-01-01

    Reliable imaging biomarkers of response to therapy in acute stroke are needed. The final infarct volume and percent of early reperfusion have been used for this purpose. Early fluctuation in stroke size is a recognized phenomenon, but its utility as a biomarker for response to therapy has not been established. This study examined the clinical relevance of early change in stroke volume and compared it with the final infarct volume and percent of early reperfusion in identifying early neurologic improvement (ENI). Acute stroke patients, enrolled between 2013 and 2014 with serial magnetic resonance imaging (MRI) scans (pretreatment baseline, 2 h post, and 24 h post), who received thrombolysis were included in the analysis. Early change in stroke volume, infarct volume at 24 h on diffusion, and percent of early reperfusion were calculated from the baseline and 2 h MRI scans were compared. ENI was defined as ≥4 point decrease in National Institutes of Health Stroke Scales within 24 h. Logistic regression models and receiver operator characteristics analysis were used to compare the efficacy of 3 imaging biomarkers. Serial MRIs of 58 acute stroke patients were analyzed. Early change in stroke volume was significantly associated with ENI by logistic regression analysis (OR 0.93, p = 0.048) and remained significant after controlling for stroke size and severity (OR 0.90, p = 0.032). Thus, for every 1 mL increase in stroke volume, there was a 10% decrease in the odds of ENI, while for every 1 mL decrease in stroke volume, there was a 10% increase in the odds of ENI. Neither infarct volume at 24 h nor percent of early reperfusion were significantly associated with ENI by logistic regression. Receiver-operator characteristic analysis identified early change in stroke volume as the only biomarker of the 3 that performed significantly different than chance (p = 0.03). Early fluctuations in stroke size may represent a more reliable biomarker for response to therapy than the

  9. Correlation between aerosol therapy in early childhood and Molar Incisor Hypomineralisation.

    PubMed

    Loli, D; Costacurta, M; Maturo, P; Docimo, R

    2015-03-01

    To evaluate the correlation between the use of aerosol therapy in early childhood and the presence of Molar Incisor Hypomineralisation (MIH). a retrospective case-control study in which a group (cases) consisted of children from 6 to 13 years with MIH visited at the unit of Pediatric Dentistry of the Policlinico Tor Vergata (Rome, Italy), and a group (controls) consisted of an equal number of children of the same age without MIH. Data about the aerosol therapy and the presence of MIH were obtained respectively by medical history and intraoral clinical examination. Collected data underwent statistical analysis using mainly non-parametric tests (p < 0.05). In the study were included 182 patients, of which 91 (46 males, 51%) were children with MIH (cases), and 91 (46 males, 51%) were children without MIH (controls). In the group of patients with MIH, in the early childhood, 12 (13.1%) never had aerosol therapy, 6 (6.6%) underwent aerosol therapy less than 7 days per year, 22 (24.2%) from 8 to 15 days per year, 22 (24.2%) from 16 to 45 days a year, and 29 (31.9%) more than 45 days per year. In the control group, in the early childhood, 9 (9.9%) never had aerosol therapy, 29 (31.9%) underwent aerosol therapy less than 7 days per year, 26 (28.6%) from 8 to 15 days per year, 20 (22.0%) from 16 to 45 days a year and 7 (7.6%) more than 45 days per year. the risk of developing MIH in children undergoing intensive use of aerosol therapy with respect to those receiving a less intensive use resulted in an odds ratio of 3.19 (p <0.001) in the general population, 4.83 (p < 0.001) in males and was not statistically significant in females (p = 0.132). The Spearman correlation between aerosol therapy and MIH was 0.278 (p < 0.001) in the general population, 0.372 (p < 0.001) in male, and it was not statistically significant (p = 0.08) in female subjects. Aerosol therapy carried out in early childhood appears to be a risk factor for the development of MIH, particularly in male

  10. Early response in cognitive-behavior therapy for syndromes of medically unexplained symptoms.

    PubMed

    Kleinstäuber, Maria; Lambert, Michael J; Hiller, Wolfgang

    2017-05-25

    Early dramatic treatment response suggests a subset of patients who respond to treatment before most of it has been offered. These early responders tend to be over represented among those who are well at termination and at follow-up. Early response patterns in psychotherapy have been investigated only for a few of mental disorders so far. The main aim of the current study was to examine early response after five therapy-preparing sessions of a cognitive behavior therapy (CBT) for syndromes of medically unexplained symptoms (MUS). In the context of a randomized, waiting-list controlled trial 48 patients who suffered from ≥3 MUS over ≥6 months received 5 therapy-preparing sessions and 20 sessions of CBT for somatoform disorders. They completed self-report scales of somatic symptom severity (SOMS-7 T), depression (BDI-II), anxiety (BSI), illness anxiety and behavior (IAS) at pre-treatment, after 5 therapy-preparing sessions (FU-5P) and at therapy termination (FU-20 T). The current analyses are based on data from the treatment arm only. Repeated measure ANOVAs revealed a significant decrease of depression (d = 0.34), anxiety (d = 0.60), illness anxiety (d = 0.38) and illness behavior (d = 0.42), but no change of somatic symptom severity (d = -0.03) between pre-treatment and FU-5P. Hierarchical linear multiple regression analyses showed that symptom improvements between pre-treatment and FU-5P predict a better outcome at therapy termination for depression and illness anxiety, after controlling for pre-treatment scores. Mixed-effect ANOVAs revealed significant group*time interaction effects indicating differences in the course of symptom improvement over the therapy between patients who fulfilled a reliable change (i.e., early response) during the 5 therapy-preparing sessions and patients who did not reach an early reliable change. Demographic or clinical variables at pre-treatment were not significantly correlated with differential scores between pre

  11. Predictors of early discontinuation of basal insulin therapy in type 2 diabetes in primary care.

    PubMed

    Kostev, K; Dippel, F W; Rathmann, W

    2016-04-01

    To identify patient-related characteristics and other impact factors predicting early discontinuation of basal insulin therapy in type 2 diabetes in primary care. A total of 4837 patients who started basal insulin therapy (glargine: n=3175; NPH: n=1662) in 1072 general and internal medicine practices throughout Germany were retrospectively analyzed (Disease Analyser Database: 01/2008-03/2014). Early discontinuation was defined as switching back to oral antidiabetic drugs (OAD) therapy within 90 days after first basal insulin prescription (index date, ID). Patient records were assessed 365 days prior and post ID. Logistic regression models were used to adjust for age, sex, diabetes duration, diabetologist care, disease management program participation, HbA1c, and comorbidity. Within 3 months after ID, 202 (6.8%) of glargine patients switched back to OAD (NPH: 130 (8.5%); p<0.05). In multivariable logistic regression, predictors of early basal insulin discontinuation were ≥1 documented hypoglycemia before ID (adjusted Odds ratio; 95% CI: 2.20; 1.27-3.82), diagnosed depression (1.31; 1.01-1.70) and referrals to specialists within 90 days after ID (2.06; 1.61-2.63). Diabetologist care (0.57; 0.36-0.89) and glargine treatment (vs. NPH: 0.78; 0.61-0.98) were related to a lower odds of having early insulin discontinuation. Less than 10% of type 2 diabetes patients switched back to oral antidiabetic drugs within 90 days after start of basal insulin therapy. In particular, patients with baseline depression and frequent or severe hypoglycemia have a higher likelihood for early discontinuation of basal insulin, whereas use of insulin glargine and diabetologist care are related to an increased chance of continuous insulin treatment. Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

  12. The History of Parkinson's Disease: Early Clinical Descriptions and Neurological Therapies

    PubMed Central

    Goetz, Christopher G.

    2011-01-01

    Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease. PMID:22229124

  13. Sildenafil citrate therapy for severe early-onset intrauterine growth restriction.

    PubMed

    von Dadelszen, P; Dwinnell, S; Magee, L A; Carleton, B C; Gruslin, A; Lee, B; Lim, K I; Liston, R M; Miller, S P; Rurak, D; Sherlock, R L; Skoll, M A; Wareing, M M; Baker, P N

    2011-04-01

    Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)< 5th percentile] and either the gestational age was <25(+0) weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil-naive early-onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early-onset IUGR-complicated pregnancies. © 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.

  14. Endoscopic therapy for early gastric cancer: Standard techniques and recent advances in ESD

    PubMed Central

    Kume, Keiichiro

    2014-01-01

    The technique of endoscopic submucosal dissection (ESD) is now a well-known endoscopic therapy for early gastric cancer. ESD was introduced to resect large specimens of early gastric cancer in a single piece. ESD can provide precision of histologic diagnosis and can also reduce the recurrence rate. However, the drawback of ESD is its technical difficulty, and, consequently, it is associated with a high rate of complications, the need for advanced endoscopic techniques, and a lengthy procedure time. Various advances in the devices and techniques used for ESD have contributed to overcoming these drawbacks. PMID:24914364

  15. Cellular Antiviral Factors that Target Particle Infectivity of HIV-1.

    PubMed

    Goffinet, Christine

    2016-01-01

    In the past decade, the identification and characterization of antiviral genes with the ability to interfere with virus replication has established cell-intrinsic innate immunity as a third line of antiviral defense in addition to adaptive and classical innate immunity. Understanding how cellular factors have evolved to inhibit HIV-1 reveals particularly vulnerable points of the viral replication cycle. Many, but not all, antiviral proteins share type I interferon-upregulated expression and sensitivity to viral counteraction or evasion measures. Whereas well-established restriction factors interfere with early post-entry steps and release of HIV-1, recent research has revealed a diverse set of proteins that reduce the infectious quality of released particles using individual, to date poorly understood modes of action. These include induction of paucity of mature glycoproteins in nascent virions or self-incorporation into the virus particle, resulting in poor infectiousness of the virion and impaired spread of the infection. A better understanding of these newly discovered antiviral factors may open new avenues towards the design of drugs that repress the spread of viruses whose genomes have already integrated.

  16. Effect of early statin therapy after acute coronary syndromes: a concise review of the recent data.

    PubMed

    Bybee, Kevin A; Wright, R Scott; Kopecky, Stephen L

    2002-01-01

    HMG Co-A reductase inhibitors(statins) have been shown, in three large randomized trials, to decrease adverse cardiac events in patients with clinically evident coronary artery disease. All of these trials have excluded patients with an acute coronary syndrome within the three months prior to enrollment. Statin therapy is thought to stabilize coronary plaque and decrease the risk of plaque rupture. Statins have been shown to quickly reduce levels of LDL-C in addition to altering systemic inflammatory responses, improving endothelial function, and reducing platelet aggregation and activation. These mechanisms are potentially beneficial in the setting of acute coronary syndromes, a time of profound plaque instability. There is a growing body of evidence supporting the early initiation of statin therapy in the setting of acute coronary syndromes. This paper reviews the available data from randomized-controlled trials and observational studies evaluating the effect of early statin initiation during, or soon following, an acute coronary syndrome.

  17. Metacognitive Reflection and Insight Therapy for Early Psychosis: A preliminary study of a novel integrative psychotherapy.

    PubMed

    Vohs, Jenifer L; Leonhardt, Bethany L; James, Alison V; Francis, Michael M; Breier, Alan; Mehdiyoun, Nikki; Visco, Andrew C; Lysaker, Paul H

    2018-05-01

    Poor insight impedes treatment in early phase psychosis (EPP). This manuscript outlines preliminary findings of an investigation of the novel metacognitively oriented integrative psychotherapy, Metacognitive Reflection and Insight Therapy, for individuals with early phase psychosis (MERIT-EP). Twenty adults with EPP and poor insight were randomized to either six months of MERIT-EP or treatment as usual (TAU). Therapists were trained and therapy was successfully delivered under routine, outpatient conditions. Insight, assessed before and after treatment, revealed significant improvement for the MERIT-EP, but not TAU, group. These results suggest MERIT-EP is feasible to deliver, accepted by patients, and leads to clinically significant improvements in insight. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer's disease therapeutics.

    PubMed

    de la Monte, Suzanne M

    Evaluation of Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol . 2011 Sep 12. Alzheimer's disease is associated with brain insulin deficiency and insulin resistance, similar to the problems in diabetes. If insulin could be supplied to the brain in the early stages of Alzheimer's, subsequent neurodegeneration might be prevented. Administering systemic insulin to elderly non-diabetics poses unacceptable risks of inadvertant hypoglycemia. However, intranasal delivery directs the insulin into the brain, avoiding systemic side-effects. This pilot study demonstrates both efficacy and safety of using intranasal insulin to treat early Alzheimer's and mild cognitive impairment, i.e. the precursor to Alzheimer's. Significant improvements in learning, memory, and cognition occured within a few months, but without intranasal insulin, brain function continued to deteriorate in measurable degrees. Intranasal insulin therapy holds promise for halting progression of Alzheimer's disease.

  19. [The importance of early exercise therapy in the treatment of Colles' fracture. A clinically controlled study].

    PubMed

    Grønlund, B; Harreby, M S; Kofoed, R; Rasmussen, L

    1990-08-27

    Forty patients participated in a study of the importance of early occupational therapy for the prognosis in stable Colles' fractures. Seventeen patients were treated by an occupational therapist 1-3 days after the injury, and the need for appliances and home-care was estimated. Twenty-three patients completed the usual treatment. Five weeks after the injury, we found significantly (p less than 0.05) better function of the hand in the 17 patients with early occupational therapy. This difference in function could not be found after 13 weeks. The rate of complications was the same in the two groups. The results indicate that contact with the occupational therapist shortly after the injury is valuable in patients with stable Colles' fractures.

  20. Molecular Diagnostics of Copper-Transporting Protein Mutations Allows Early Onset Individual Therapy of Menkes Disease.

    PubMed

    Králík, L; Flachsová, E; Hansíková, H; Saudek, V; Zeman, J; Martásek, P

    2017-01-01

    Menkes disease is a severe X-linked recessive disorder caused by a defect in the ATP7A gene, which encodes a membrane copper-transporting ATPase. Deficient activity of the ATP7A protein results in decreased intestinal absorption of copper, low copper level in serum and defective distribution of copper in tissues. The clinical symptoms are caused by decreased activities of copper-dependent enzymes and include neurodegeneration, connective tissue disorders, arterial changes and hair abnormalities. Without therapy, the disease is fatal in early infancy. Rapid diagnosis of Menkes disease and early start of copper therapy is critical for the effectiveness of treatment. We report a molecular biology-based strategy that allows early diagnosis of copper transport defects and implementation of individual therapies before the full development of pathological symptoms. Low serum copper and decreased activity of copperdependent mitochondrial cytochrome c oxidase in isolated platelets found in three patients indicated a possibility of functional defects in copper-transporting proteins, especially in the ATPA7 protein, a copper- transporting P-type ATPase. Rapid mutational screening of the ATP7A gene using high-resolution melting analysis of DNA indicated presence of mutations in the patients. Molecular investigation for mutations in the ATP7A gene revealed three nonsense mutations: c.2170C>T (p.Gln724Ter); c.3745G>T (p.Glu1249Ter); and c.3862C>T (p.Gln1288Ter). The mutation c.3745G>T (p.Glu1249Ter) has not been identified previously. Molecular analysis of the ATOX1 gene as a possible modulating factor of Menkes disease did not reveal presence of pathogenic mutations. Molecular diagnostics allowed early onset of individual therapies, adequate genetic counselling and prenatal diagnosis in the affected families.

  1. Early Stage Breast Cancer in Older Women: Predictors and Outcomes of Therapy

    DTIC Science & Technology

    2001-10-01

    undergoing at least the The use of breast-conserving surgery increased during minimum appropriate primary treatment (defined, in the early 1980s ,3...remained generally stable during the late accordance with the recommendations of a National 1980s ,4’, and increased further from about 1990 Institutes of...receiving appropriate primary therapy was about 88% was classified as white, black, or other. The size of until the late 1980s (figure 1); it then

  2. Antifungal and antiviral products of marine organisms

    PubMed Central

    Cheung, Randy Chi Fai; Pan, Wen Liang; Chan, Yau Sang; Yin, Cui Ming; Dan, Xiu Li; Wang, He Xiang; Fang, Evandro Fei; Lam, Sze Kwan; Ngai, Patrick Hung Kui; Xia, Li Xin; Liu, Fang; Ye, Xiu Yun; Zhang, Guo Qing; Liu, Qing Hong; Sha, Ou; Lin, Peng; Ki, Chan; Bekhit, Adnan A; Bekhit, Alaa El-Din; Wan, David Chi Cheong

    2017-01-01

    Marine organisms including bacteria, fungi, algae, sponges, echinoderms, mollusks, and cephalochordates produce a variety of products with antifungal activity including bacterial chitinases, lipopeptides, and lactones; fungal (−)-sclerotiorin and peptaibols, purpurides B and C, berkedrimane B and purpuride; algal gambieric acids A and B, phlorotannins; 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol, spongistatin 1, eurysterols A and B, nortetillapyrone, bromotyrosine alkaloids, bis-indole alkaloid, ageloxime B and (−)-ageloxime D, haliscosamine, hamigeran G, hippolachnin A from sponges; echinoderm triterpene glycosides and alkene sulfates; molluscan kahalalide F and a 1485-Da peptide with a sequence SRSELIVHQR; and cepalochordate chitotriosidase and a 5026.9-Da antifungal peptide. The antiviral compounds from marine organisms include bacterial polysaccharide and furan-2-yl acetate; fungal macrolide, purpurester A, purpurquinone B, isoindolone derivatives, alterporriol Q, tetrahydroaltersolanol C and asperterrestide A, algal diterpenes, xylogalactofucan, alginic acid, glycolipid sulfoquinovosyldiacylglycerol, sulfated polysaccharide p-KG03, meroditerpenoids, methyl ester derivative of vatomaric acid, lectins, polysaccharides, tannins, cnidarian zoanthoxanthin alkaloids, norditerpenoid and capilloquinol; crustacean antilipopolysaccharide factors, molluscan hemocyanin; echinoderm triterpenoid glycosides; tunicate didemnin B, tamandarins A and B and; tilapia hepcidin 1–5 (TH 1–5), seabream SauMx1, SauMx2, and SauMx3, and orange-spotted grouper β-defensin. Although the mechanisms of antifungal and antiviral activities of only some of the afore-mentioned compounds have been elucidated, the possibility to use those known to have distinctly different mechanisms, good bioavailability, and minimal toxicity in combination therapy remains to be investigated. It is also worthwhile to test the marine antimicrobials for possible synergism with existing drugs. The

  3. Early use of negative pressure therapy in combination with silver dressings in a difficult breast abscess.

    PubMed

    Richards, Alastair J; Hagelstein, Sue M; Patel, Girish K; Ivins, Nicola M; Sweetland, Helen M; Harding, Keith G

    2011-12-01

    Combining silver-based dressings with negative pressure therapy after radical excision of chronically infected breast disease is a novel application of two technologies. One patient with complex, chronic, infected breast disease underwent radical excision of the affected area and was treated early with a combination of silver-based dressings and topical negative pressure therapy. The wound was then assessed sequentially using clinical measurements of wound area and depth, pain severity scores and level of exudation. It is possible to combine accepted techniques with modern dressing technologies that result in a positive outcome. In this case, the combination of a silver-based dressing with negative pressure therapy following radical excision proved safe and was well tolerated by the patient. Full epithelisation of the wound was achieved and there was no recurrence of the infection for the duration of the treatment. © 2011 The Authors. © 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc.

  4. Indication for and frequency of early orthodontic therapy or interceptive measures.

    PubMed

    Schopf, Peter

    2003-05-01

    The early treatment of nonskeletal and skeletal orthodontic anomalies in the deciduous and early mixed dentition is intended to prevent the development of pronounced anomalies in the late mixed and permanent dentition with the ultimate aim of reducing or even eliminating the need for later orthodontic treatment. There is a general consensus in the international literature that early therapy is indicated in cases of anterior and lateral crossbite and Class III malocclusion, and possibly for extreme forms of mandibular retrognathism (overjet > or =10 mm) and of open bite. However, evidence of the efficiency of early orthodontic measures is just as rare as studies providing serviceable information on the incidence of tooth malalignments and malocclusions in the deciduous and early mixed dentition, some of whose findings are in any case highly divergent. This makes it substantially more difficult to draw conclusions on the extent to which early orthodontic therapy may be indicated. In order to obtain information on the incidence of nonskeletal and skeletal orthodontic problems constituting a treatment need, 2326 first-year schoolchildren aged between 6 and 7 years were examined in Frankfurt am Main and in the Rural District of Offenbach. In only 14.7% of the children were no relevant orthodontic findings recorded. 77.2% displayed mild to severe dysgnathic symptoms, though without early orthodontic therapy being considered indicated. Treatment with orthodontic appliances was considered urgent for 187 of the children (8.04%). With 8.3% and 7.9% respectively, lateral and anterior crossbite were top of the list of anomalies with an urgent treatment need. Among the patients with lateral crossbite, the prognostically less favorable unilateral form was recorded approximately four times more often than the bilateral form. Markedly increased sagittal overjet > or =10 mm) was registered in only 1.4% of the children, and negative overjet (Class III) (with the exception of edge

  5. Information Needs of Older Women With Early-Stage Breast Cancer When Making Radiation Therapy Decisions.

    PubMed

    Wang, Shi-Yi; Kelly, Gabrielle; Gross, Cary; Killelea, Brigid K; Mougalian, Sarah; Presley, Carolyn; Fraenkel, Liana; Evans, Suzanne B

    2017-07-15

    To identify the information older women with early-stage breast cancer need when making radiation therapy decisions, and who patients identify as the main decision maker. We surveyed (through face-to-face interview, telephone, or mail) women aged ≥65 years who received lumpectomy and were considering or receiving adjuvant radiation therapy for early-stage breast cancer. The survey instrument was constructed with input from patient and professional advisory committees, including breast cancer survivors, advocates of breast cancer care and aging, clinicians, and researchers. Participants rated the importance (on a 4-point scale) of 24 statements describing the benefits, side effects, impact on daily life, and other issues of radiation therapy in relation to radiation therapy decision making. Participants also designated who was considered the key decision maker. The response rate was 56.4% (93 of 165). Mean age was 72.5 years, ranging from 65 to 93 years. More than 96% of participants indicated they were the main decision maker on receiving radiation therapy. There was wide variation in information needs regarding radiation therapy decision making. Participants rated a mean of 18 (range, 3-24) items as "essential." Participants rated items related to benefits highest, followed by side effects. Participants who were older than 75 years rated 13.9 questions as essential, whereas participants aged ≤74 years rated 18.7 as essential (P=.018). Older women desire information and have more agency and input in the decision-making process than prior literature would suggest. The variation in information needs indicates that future decision support tools should provide options to select what information would be of interest to the participants. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Original Research: Metabolic alterations from early life thyroxine replacement therapy in male Ames dwarf mice are transient.

    PubMed

    Darcy, Justin; Fang, Yimin; Hill, Cristal M; McFadden, Sam; Sun, Liou Y; Bartke, Andrzej

    2016-10-01

    Ames dwarf mice are exceptionally long-lived due to a Prop1 loss of function mutation resulting in deficiency of growth hormone, thyroid-stimulating hormone and prolactin. Deficiency in thyroid-stimulating hormone and growth hormone leads to greatly reduced levels of circulating thyroid hormones and insulin-like growth factor 1, as well as a reduction in insulin secretion. Early life growth hormone replacement therapy in Ames dwarf mice significantly shortens their longevity, while early life thyroxine (T4) replacement therapy does not. Possible mechanisms by which early life growth hormone replacement therapy shortens longevity include deleterious effects on glucose homeostasis and energy metabolism, which are long lasting. A mechanism explaining why early life T4 replacement therapy does not shorten longevity remains elusive. Here, we look for a possible explanation as to why early life T4 replacement therapy does not impact longevity of Ames dwarf mice. We found that early life T4 replacement therapy increased body weight and advanced the age of sexual maturation. We also find that early life T4 replacement therapy does not impact glucose tolerance or insulin sensitivity, and any deleterious effects on oxygen consumption, respiratory quotient and heat production are transient. Lastly, we find that early life T4 replacement therapy has long-lasting effects on bone mineral density and bone mineral content. We suggest that the transient effects on energy metabolism and lack of effects on glucose homeostasis are the reasons why there is no shortening of longevity after early life T4 replacement therapy in Ames dwarf mice. © 2016 by the Society for Experimental Biology and Medicine.

  7. The early career researcher's toolkit: translating tissue engineering, regenerative medicine and cell therapy products.

    PubMed

    Rafiq, Qasim A; Ortega, Ilida; Jenkins, Stuart I; Wilson, Samantha L; Patel, Asha K; Barnes, Amanda L; Adams, Christopher F; Delcassian, Derfogail; Smith, David

    2015-11-01

    Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in tissue engineering and regenerative medicine translation, we discuss common pitfalls associated with translational research, providing practical solutions and important considerations which will aid process and product development. Suggestions range from effective project management, consideration of key manufacturing, clinical and regulatory matters and means of exploiting research for successful commercialization.

  8. Predicting early positive change in multisystemic therapy with youth exhibiting antisocial behaviors.

    PubMed

    Tiernan, Kristine; Foster, Sharon L; Cunningham, Phillippe B; Brennan, Patricia; Whitmore, Elizabeth

    2015-03-01

    This study examined individual and family characteristics that predicted early positive change in the context of Multisystemic Therapy (MST). Families (n = 185; 65% male; average youth age 15 years) receiving MST in community settings completed assessments at the outset of treatment and 6-12 weeks into treatment. Early positive changes in youth antisocial behavior were assessed using the caregiver report on the Child Behavior Checklist Externalizing Behaviors subscale and youth report on the Self-Report Delinquency Scale. Overall, families showed significant positive changes by 6-12 weeks into treatment; these early changes were maintained into midtreatment 6-12 weeks later. Families who exhibited clinically significant gains early in treatment were more likely to terminate treatment successfully compared with those who did not show these gains. Low youth internalizing behaviors and absence of youth drug use predicted early positive changes in MST. High levels of parental monitoring and low levels of affiliation with deviant peers (mechanisms known to be associated with MST success) were also associated with early positive change. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

  9. Flavocoxid exerts a potent antiviral effect against hepatitis B virus.

    PubMed

    Pollicino, Teresa; Musolino, Cristina; Irrera, Natasha; Bitto, Alessandra; Lombardo, Daniele; Timmoneri, Martina; Minutoli, Letteria; Raimondo, Giovanni; Squadrito, Giovanni; Squadrito, Francesco; Altavilla, Domenica

    2018-01-01

    Flavocoxid is a proprietary blend of two flavonoids, baicalin and catechin, and recent evidence has shown that bioflavonoids may exert antiviral activities. The potential antiviral activity of Flavocoxid against hepatitis B virus (HBV) was evaluated. Additionally, it was investigated if Flavocoxid used in combination with Entecavir could potentiate its anti-HBV activity. Hepatoma cells replicating HBV were treated with Flavocoxid, or Entecavir alone or in combination for up to 5 days. Viral replicative intermediates, transcripts, and cccDNA levels were evaluated in HBV-replicating cells by real-time PCR, Southern and Northern blotting. Expression profiling was performed using TaqMan low-density arrays. Flavocoxid treatment induced a reduction of HBV replicative intermediates, the amount of transcripts, and HBsAg levels. Flavocoxid and Entecavir combination therapy further decreased the amount of HBV replicative intermediates, compared to Flavocoxid alone. Importantly, Flavocoxid alone or in combination with Entecavir also induced a reduction of cccDNA. Gene-expression analysis showed that Flavocoxid activates type I IFNs-signaling and dampens the HBV-induced inflammatory response. Flavocoxid inhibits HBV replication by targeting multiple steps of viral life cycle. These results indicate that the antiviral activity of Entecavir is potentiated by Flavocoxid, suggesting that this medical food might be considered as an adjuvant for anti-HBV therapy.

  10. Early Cutaneous Leishmaniasis Patients Infected With Leishmania braziliensis Express Increased Inflammatory Responses After Antimony Therapy.

    PubMed

    Costa, Rúbia S; Carvalho, Lucas P; Campos, Taís M; Magalhães, Andréa S; Passos, Sara T; Schriefer, Albert; Silva, Juliana A; Lago, Ednaldo; Paixão, Camilla S; Machado, Paulo; Scott, Phillip; Carvalho, Edgar M

    2018-02-14

    Early cutaneous leishmaniasis (ECL) is characterized by a nonulcerated papular lesion and illness duration less than 30 days. Approximately 4 weeks later, the cutaneous leishmaniasis (CL) ulcers appear. We were surprised to find that failure after antimony therapy (Sb5) is higher in ECL than CL. We hypothesize that the inflammatory response in ECL patients may increase during Sb5 therapy, which leads to treatment failure. A cohort of 44 ECL patients infected by Leishmania braziliensis was established to evaluate the response to Sb5 and to compare immunologic responses in ECL patients with CL and healthy subjects. A hierarchical clustering based on cytokine levels showed a weak positive correlation between proinflammatory cytokine levels and those patients that failed Sb5 treatment. Although Sb5 therapy decreased interferon-γ and tumor necrosis factor levels in CL patients, we were surprised to find that an increase in these cytokines was observed in ECL patients. Moreover, interleukin (IL)-10 was less able to down-modulate immune responses in ECL. The enhanced production of proinflammatory cytokines, due in part to the decreased ability of IL-10 to down-modulate immune response during therapy in ECL, promotes the development and persistence of leishmania ulcer despite antimony therapy. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  11. COST-EFFECTIVENESS OF EARLY NUTRITIONAL THERAPY IN MALNOURISHED ADULT PATIENTS IN A HIGH COMPLEXITY HOSPITAL.

    PubMed

    Giraldo Giraldo, Nubia Amparo; Vásquez Velásquez, Johanna; Roldán Cano, Paula Andrea; Ospina Astudillo, Carolina; Sosa Cardona, Yuliet Paulina

    2015-12-01

    hospital malnutrition is a frequent worldwide problem and its potential issues related include increased complications, length of stay, mortality, and healthcare costs. the aim of this study was to establish the cost-effectiveness of early nutritional therapy for malnourished patients in a high complexity hospital. this analytical study with economic assessment included 227 adult hospitalised and malnourished according to the Subjective Global Assessment. The cohort prospective received Early Nutrition Therapy (ENT), whereas the cohort retrospective received Delayed Nutrition Therapy (DNT). The measures of cost-effectiveness included costs by: length of stay, complications and discharge condition. the cohorts were similar in demographic and clinical characteristics, except that the median age, for the ENT was 61 years (interquartile range [IQR]: 48-71) and for the DNT was 55 years (IQR: 44-67) (p = 0.024). The median length of stay was lower in the ENT (11 days, IQR: 7-17) than in the DNT (18 days, IQR: 10-28) (p < 0.001). The cost per patient discharged alive was US $ 10,261.55 in the ENT and US $ 15,553.11 in the DNT (p=0.043); the cost per patient with complications was US $ 13,663.90 in the ENT and US $ 17,860.32 in the DNT (p= 0.058). ENT increased the likelihood of being discharged alive, RR adjusted=0.31; 95% confidence interval (CI): 0.1; 0.6; (p<0.001) and decreased the likelihood of complications RR crude=0.8; 95% CI: 0.6; 0.9; (p=0.006). early nutritional therapy for malnourished adult patients appears to be cost-effective because it can reduce the length of stay, complications, mortality and associated costs. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  12. Role of Chemotherapy and Targeted Therapy in Early-Stage Non-Small Cell Lung Cancer.

    PubMed

    Gadgeel, Shirish M

    2017-01-01

    On the basis of several randomized trials and meta-analyses, adjuvant chemotherapy is the accepted standard of care for certain patients with early-stage non-small cell lung cancer (NSCLC). Patients with stage II, IIIA, or large (≥ 4 cm) IB tumors are candidates for adjuvant chemotherapy. The survival improvement with adjuvant chemotherapy is approximately 5% at 5 years, though certain trials have suggested that it can be 8% to 10%. Neoadjuvant chemotherapy also has shown a survival advantage, though the volume of data with this approach is far less than that of adjuvant chemotherapy. The combination of cisplatin and vinorelbine is the most well-studied regimen, but current consensus is to use four cycles of any of the platinum-based chemotherapy regimens commonly used as front-line therapy for patients with advanced-stage NSCLC. Trials to define biomarkers that can predict benefit from adjuvant chemotherapy have not been successful, but results of other such trials are still awaited. On the basis of the benefit observed with targeted agents in patients with advanced-stage disease and driver genetic alterations in their tumors, ongoing trials are evaluating the utility of these targeted agents as adjuvant therapy. Similarly, clinical benefit observed with checkpoint inhibitors has prompted assessment of these drugs in patients with early-stage NSCLC. It is very likely, in the future, that factors other than the anatomy of the tumor will be used to select patients with early-stage NSCLC for systemic therapy and that the choice of systemic therapy will extend beyond platinum-based chemotherapy.

  13. Effectiveness of early adalimumab therapy in psoriatic arthritis patients from Reuma.pt - EARLY PsA.

    PubMed

    Santos, Helena; Eusébio, Mónica; Borges, Joana; Gonçalves, Diana; Ávila-Ribeiro, Pedro; Faria, Daniela Santos; Lopes, Carina; Rovisco, João; Águeda, Ana; Nero, Patrícia; Valente, Paula; Cravo, Ana Rita; Santos, Maria José

    2017-01-01

    had no effect on PsARC response over 2 years of follow-up. Persistence on ADA was similar in both groups. Conclusion Early PsA patients had a greater chance of improvement after ADA therapy and better functional outcome, and achieved PsARC response more rapidly than late PsA. In this cohort, comedication with csDMARDs was beneficial over 2 years.

  14. A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs

    PubMed Central

    Karlas, Alexander; Berre, Stefano; Couderc, Thérèse; Varjak, Margus; Braun, Peter; Meyer, Michael; Gangneux, Nicolas; Karo-Astover, Liis; Weege, Friderike; Raftery, Martin; Schönrich, Günther; Klemm, Uwe; Wurzlbauer, Anne; Bracher, Franz; Merits, Andres; Meyer, Thomas F.; Lecuit, Marc

    2016-01-01

    Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents. PMID:27177310

  15. A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.

    PubMed

    Karlas, Alexander; Berre, Stefano; Couderc, Thérèse; Varjak, Margus; Braun, Peter; Meyer, Michael; Gangneux, Nicolas; Karo-Astover, Liis; Weege, Friderike; Raftery, Martin; Schönrich, Günther; Klemm, Uwe; Wurzlbauer, Anne; Bracher, Franz; Merits, Andres; Meyer, Thomas F; Lecuit, Marc

    2016-05-12

    Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents.

  16. Optimizing Tactics for Use of the U.S. Antiviral Strategic National Stockpile for Pandemic Influenza

    PubMed Central

    Dimitrov, Nedialko B.; Goll, Sebastian; Hupert, Nathaniel; Pourbohloul, Babak; Meyers, Lauren Ancel

    2011-01-01

    In 2009, public health agencies across the globe worked to mitigate the impact of the swine-origin influenza A (pH1N1) virus. These efforts included intensified surveillance, social distancing, hygiene measures, and the targeted use of antiviral medications to prevent infection (prophylaxis). In addition, aggressive antiviral treatment was recommended for certain patient subgroups to reduce the severity and duration of symptoms. To assist States and other localities meet these needs, the U.S. Government distributed a quarter of the antiviral medications in the Strategic National Stockpile within weeks of the pandemic's start. However, there are no quantitative models guiding the geo-temporal distribution of the remainder of the Stockpile in relation to pandemic spread or severity. We present a tactical optimization model for distributing this stockpile for treatment of infected cases during the early stages of a pandemic like 2009 pH1N1, prior to the wide availability of a strain-specific vaccine. Our optimization method efficiently searches large sets of intervention strategies applied to a stochastic network model of pandemic influenza transmission within and among U.S. cities. The resulting optimized strategies depend on the transmissability of the virus and postulated rates of antiviral uptake and wastage (through misallocation or loss). Our results suggest that an aggressive community-based antiviral treatment strategy involving early, widespread, pro-rata distribution of antivirals to States can contribute to slowing the transmission of mildly transmissible strains, like pH1N1. For more highly transmissible strains, outcomes of antiviral use are more heavily impacted by choice of distribution intervals, quantities per shipment, and timing of shipments in relation to pandemic spread. This study supports previous modeling results suggesting that appropriate antiviral treatment may be an effective mitigation strategy during the early stages of future influenza

  17. Prospective randomised trial of early cytotoxic therapy for recurrent colorectal carcinoma detected by serum CEA.

    PubMed Central

    Hine, K R; Dykes, P W

    1984-01-01

    Of 663 patients treated with radical surgery for colorectal cancer, 52 showed a progressive rise in serum carcinoembryonic antigen (CEA) with no other evidence of recurrent disease and were randomised in a prospective study of chemotherapy. Twenty six patients in the treatment group received 5FU and methyl CCNU from the time of randomisation and the remaining 26 controls were given further therapy only if there were clinical indications. All patients were followed for five years or until their death and all but one (control) developed clinical evidence of recurrence. Overall there was no significant difference between the two groups with respect to disease free interval and survival. Whereas the rise in CEA in controls was generally progressive, marked inflections on the CEA curves were seen in the majority of patients receiving early treatment. Eight of 26 treated patients showed a fall in CEA of greater than 20% two months after starting therapy. These patients had a median disease free interval of 90 weeks and a median survival of 107 weeks, these figures being longer than those of treated patients who did not show a fall in CEA and control patients. The serum CEA therefore appeared to give important prognostic information in patients receiving cytotoxic treatment. Early therapy was generally well tolerated. PMID:6376291

  18. What You Should Know about Flu Antiviral Drugs

    MedlinePlus

    ... Other What You Should Know About Flu Antiviral Drugs Language: English (US) Español Recommend on Facebook Tweet ... used to treat flu illness. What are antiviral drugs? Antiviral drugs are prescription medicines (pills, liquid, an ...

  19. Early antiretroviral therapy: rationale, protease inhibitor-sparing regimens and once daily dosing.

    PubMed

    Gatell, J M

    1998-01-01

    In 1998 it seems reasonable and widely accepted that all human immunodeficiency virus type 1 (HIV-1)-infected patients willing to be treated may benefit from receiving antiretroviral therapy. Only those with undetectable plasma HIV-1 RNA, normal CD4 lymphocyte counts and lack of markers of immunological system activation may be possible exceptions. The rationale supporting the early initiation of antiretroviral therapy are (i) data on viral dynamics; (ii) preliminary data pointing toward a better and a quicker restoration of immune function when treatment is initiated in very early stages (during or within a few weeks or months of acute symptomatic or asymptomatic HIV-1 infection); (iii) the lack of a stable viral load set-point even in patients in the early stages (CD4 > 500 cells/mm3) who have a very low viral load (< 5000 copies/ml); (iv) the relatively high likelihood of clinical progression at mid-term of the approximately 50-75% of patients in very early disease stages (CD4 > 500 cells/mm3) who have a plasma viral load above 5000 to 10,000 HIV-1 RNA copies/ml; (v) data from the Spanish Earth-1 study, which used a composite endpoint (virological, immunological or clinical progression), demonstrating that even in these very early stages of HIV-1 disease any antiretroviral therapy (double or triple combination) was better than no treatment. Even in early disease stages, a triple combination is needed to achieve a durable and profound virological and immunological response. In addition, the combination of stavudine plus didanosine has several advantages and can be considered one of the best double nucleoside combinations to combine with a protease inhibitor or with a non-nucleoside reverse transcriptase inhibitor. The INCAS study and the preliminary results of the ongoing Spanish SCAN study have demonstrated the possibility of protease inhibitor-sparing combinations for initial antiretroviral treatment, at least in selected patient subsets, such as those with a

  20. Understanding Early Decisions to Withdraw Life-Sustaining Therapy in Cardiac Arrest Survivors. A Qualitative Investigation.

    PubMed

    Dale, Craig M; Sinuff, Tasnim; Morrison, Laurie J; Golan, Eyal; Scales, Damon C

    2016-07-01

    Early withdrawal of life-sustaining therapy contributes to the majority of deaths following out-of-hospital cardiac arrest (OHCA), despite current recommendations for delayed neurological prognostication (≥72 h) after treatment with targeted temperature management. Little is known about clinicians' experiences of early withdrawal of life support decisions in patients with OHCA. To explore clinicians' experiences and perceptions of early withdrawal of life support decisions and barriers to guideline-concordant neurological prognostication in comatose survivors of OHCA treated with targeted temperature management. We conducted qualitative interviews with intensive care unit (ICU) physicians and nurses following withdrawal of life support in comatose patients with OHCA treated with targeted temperature management. The study was carried out across 18 academic and community hospitals participating in a multicenter, stepped-wedge, cluster-randomized controlled trial designed to improve quality-of-care processes for patients after OHCA in Ontario, Canada. We used a focused thematic analysis to capture barriers to guideline-concordant neurological prognostication and used these barriers to identify potentially modifiable issues. The core thematic finding was a high emotional burden of ICU family-team communication in which strong feelings inhibited information transfer and delayed decision making following OHCA. Four subthemes describing sources of communication strain were identified: (1) requests from family members to provide early outcome predictions, (2) incomplete family comprehension of critical care, (3) family requests for early withdrawal of life support based on their understanding of patients' preferences and values, and (4) family-team communication gaps related to prognostic uncertainty. Participants worried that gaps in timely and clear prognostic information contributed to surrogates' perceptions of a poor outcome and to inappropriately early decisions to

  1. A Longitudinal Assessment of Early Childhood Education with Integrated Speech Therapy for Children with Significant Language Impairment in Germany

    ERIC Educational Resources Information Center

    Ullrich, Dieter; Ullrich, Katja; Marten, Magret

    2014-01-01

    Background: In Lower Saxony, Germany, pre-school children with language- and speech-deficits have the opportunity to access kindergartens with integrated language-/speech therapy prior to attending primary school, both regular or with integrated speech therapy. It is unknown whether these early childhood education treatments are helpful and…

  2. Sensory Integration Therapy in Malaysia and Singapore: Sources of Information and Reasons for Use in Early Intervention

    ERIC Educational Resources Information Center

    Leong, H. M.; Carter, Mark; Stephenson, Jennifer

    2013-01-01

    Sensory integration (SI) therapy is a popular form of intervention for children with disabilities, particularly those with autism spectrum disorders, even though research evidence demonstrating beneficial outcomes from the use of SI therapy is limited. A questionnaire was distributed to early intervention education service providers in Malaysia…

  3. CMV pneumonia in allogeneic BMT recipients undergoing early treatment of pre-emptive ganciclovir therapy.

    PubMed

    Machado, C M; Dulley, F L; Boas, L S; Castelli, J B; Macedo, M C; Silva, R L; Pallota, R; Saboya, R S; Pannuti, C S

    2000-08-01

    The incidence, treatment and outcome of CMV interstitial pneumonia (CMV-IP) were reviewed in 139 consecutive allogeneic BMT patients undergoing extended CMV antigenemia surveillance and two different ganciclovir (GCV) strategies to control CMV infection. Nineteen cases of CMV-IP were reviewed, 16 of 63 patients (25.4%) who received early GCV treatment (ET) and three of 76 patients (3.9%) who received preemptive (PE) GCV therapy. In the ET group, the median time for occurrence of CMV-IP was 55 (range 36 to 311) days. Two patients had three episodes of CMV-IP recurrences after day +100. CMV-IP-related death occurred in two patients (15.4%). In the PE group, 41 patients received pre-emptive GCV therapy prompted by the appearance of positive antigenemia > or =2 cells. The median time for the occurrence of CMV-IP was 92 (range 48 to 197) days. Response to therapy was observed when GCV was introduced within 6 days of antigenemia positivity. The use of IVIg in association with GCV did not play a major role in response to therapy. The median time for occurrence of CMV-IP was delayed during PE strategy and the cost-effectiveness of CMV surveillance after day +100 should be investigated in this population.

  4. [Reha-Stepper locomotion therapy in early rehabilitation of paraplegic patients].

    PubMed

    Rupp, R; Eberhard, S; Schreier, R; Colombo, G

    2002-01-01

    Treadmill training with partial body weight support was shown to significantly improve the constitution and gait capacity of incomplete spinal cord injured (SCI) persons. The main requirement for application of this therapy is a sufficient capacity of the cardiovascular system. Most of the SCI patients do not comply with this requirement in the first few weeks after spinal cord injury, where spinal reflexes are frequently missing (spinal shock). To offer SCI patients a locomotion therapy at this early stage of rehabilitation we developed a novel, active tilt-table, the Reha-Stepper, that moves the lower limbs in an almost physiological manner in terms of kinematic and kinetic parameters. The tilt of the device can be continuously increased from horizontal to almost upright position adapted to the status of the patient.

  5. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy.

    PubMed

    Lally, Peter J; Montaldo, Paolo; Oliveira, Vânia; Swamy, Ravi Shankar; Soe, Aung; Shankaran, Seetha; Thayyil, Sudhin

    2018-07-01

    We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5-13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. Stabilization in early adult-onset myopia with corneal refractive therapy.

    PubMed

    González-Méijome, José M; Carracedo, Gonzalo; Lopes-Ferreira, Daniela; Faria-Ribeiro, Miguel A; Peixoto-de-Matos, Sofia C; Queirós, António

    2016-02-01

    To describe the stabilization of early adult-onset myopia in three university students after initiating orthokeratology treatment with corneal refractive therapy contact lenses. Three Caucasian early adult-onset progressing myopic subjects (1 male, 2 females) were fitted with corneal refractive therapy lenses to correct myopia between -1.50 and -2.50 D of sphere using Paragon CRT (Paragon Vision Sciences, Mesa, AZ) lenses for overnight orthokeratology. The pre-treatment refractive history from 2005 as well as refraction and axial length after treatment onset are reported over a period of 3 years between December 2009 and January 2013 with an additional year of follow-up after treatment discontinuation (January-December 2013). The peripheral refractive patterns and topographic changes are also reported individually. Treatment was successful in all three subjects achieving uncorrected visual acuity of 20/20 or better monocularly. During a period of 3 years of follow-up the subjects did not experience progression in their refractive error, nor in their axial length (measured during the last 2 years of treatment and 1 year after discontinuation). Furthermore, the subjects recovered to their baseline refraction and did not progressed further over the following year after lens wear discontinuation. We cannot attribute a causative effect to the orthokeratology treatment alone as underlying mechanism for myopia stabilization in this 3 patients. However, the present report points to the possibility of stabilization of early adult-onset myopia progression in young adults using corneal refractive therapy treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Antiviral Lectins: Selective Inhibitors of Viral Entry

    PubMed Central

    Mitchell, Carter A.; Ramessar, Koreen; O’Keefe, Barry R.

    2017-01-01

    Many natural lectins have been reported to have antiviral activity. As some of these have been put forward as potential development candidates for preventing or treating viral infections, we have set out in this review to survey the literature on antiviral lectins. The review groups lectins by structural class and class of source organism we also detail their carbohydrate specificity and their reported antiviral activities. The review concludes with a brief discussion of several of the pertinent hurdles that heterologous proteins must clear to be useful clinical candidates and cites examples where such studies have been reported for antiviral lectins. Though the clearest path currently being followed is the use of antiviral lectins as anti-HIV microbicides via topical mucosal administration, some investigators have also found systemic efficacy against acute infections following subcutaneous administration. PMID:28322922

  8. Broad-spectrum antivirals against viral fusion

    PubMed Central

    Vigant, Frederic; Santos, Nuno C.; Lee, Benhur

    2015-01-01

    Effective antivirals have been developed against specific viruses, such as HIV, Hepatitis C virus and influenza virus. This ‘one bug–one drug’ approach to antiviral drug development can be successful, but it may be inadequate for responding to an increasing diversity of viruses that cause significant diseases in humans. The majority of viral pathogens that cause emerging and re-emerging infectious diseases are membrane-enveloped viruses, which require the fusion of viral and cell membranes for virus entry. Therefore, antivirals that target the membrane fusion process represent new paradigms for broad-spectrum antiviral discovery. In this Review, we discuss the mechanisms responsible for the fusion between virus and cell membranes and explore how broad-spectrum antivirals target this process to prevent virus entry. PMID:26075364

  9. Participatory design in the development of an early therapy intervention for perinatal stroke.

    PubMed

    Basu, Anna Purna; Pearse, Janice Elizabeth; Baggaley, Jessica; Watson, Rose Mary; Rapley, Tim

    2017-01-23

    Perinatal stroke is the leading cause of unilateral (hemiparetic) cerebral palsy, with life-long personal, social and financial consequences. Translational research findings indicate that early therapy intervention has the potential for significant improvements in long-term outcome in terms of motor function. By involving families and health professionals in the development and design stage, we aimed to produce a therapy intervention which they would engage with. Nine parents of children with hemiparesis and fourteen health professionals involved in the care of infants with perinatal stroke took part in peer review and focus groups to discuss evolving therapy materials, with revisions made iteratively. The materials and approach were also discussed at a meeting of the London Child Stroke Research Reference Group. Focus group data were coded using Normalisation Process Theory constructs to explore potential barriers and facilitators to routine uptake of the intervention. We developed the Early Therapy in Perinatal Stroke (eTIPS) program - a parent-delivered, home-based complex intervention addressing a current gap in practice for infants in the first 6 months of life after unilateral perinatal stroke and with the aim of improving motor outcome. Parents and health professionals saw the intervention as different from usual practice, and valuable (high coherence). They were keen to engage (high cognitive participation). They considered the tasks for parents to be achievable (high collective action). They demonstrated trust in the approach and felt that parents would undertake the recommended activities (high collective action). They saw the approach as flexible and adaptable (high reflexive monitoring). Following suggestions made, we added a section on involving the extended family, and obtained funding for a website and videos to supplement written materials. Focus groups with parents and health professionals provided meaningful feedback to iteratively improve the

  10. Intravenous calcitriol therapy in an early stage prevents parathyroid gland growth

    PubMed Central

    Taniguchi, Masatomo; Tokumoto, Masanori; Tsuruya, Kazuhiko; Hirakata, Hideki; Iida, Mitsuo

    2008-01-01

    Background. Both the phenotypic alterations of parathyroid (PT) cells, e.g. down-regulation of the calcium-sensing receptor, and the increase of the PT cell number in nodular hyperplasia are the main causes of refractory secondary hyperparathyroidism. It is of great importance to prevent PT growth in an early stage. Methods. To examine a more effective method of calcitriol therapy for the prevention of PT hyperplasia, we randomized haemodialysis patients with mild hyperparathyroidism to receive either daily orally administered calcitriol (n = 33) or intravenous calcitriol (n = 27) over a 12-month study period. Calcitriol was modulated so as to keep the serum intact PTH level between 100 and 150 pg/ml. Results. Both groups showed similar reductions of the serum PTH level and similar increases in serum calcium. In both groups, there were no significant changes in the serum phosphate level. Long-term daily oral calcitriol therapy failed to prevent the increase of both maximum PT volume and total volume, as assessed by ultrasonography; however, intravenous calcitriol therapy successfully suppressed this progression. In the daily, oral group, both the bone-specific alkaline phosphatase (BAP) and the N-telopeptide cross-linked of type I collagen (NTX) significantly decreased, which was probably due to the PTH suppression. However, these bone metabolism markers remained stable in the intravenous group. The total dosage of calcitriol during the study was comparable in both groups. Conclusions. These data indicate that intravenous calcitriol therapy in an early stage of secondary hyperparathyroidism is necessary to prevent PT growth and to keep a good condition of bone metabolism. PMID:18515308

  11. Early ultrasonographic evaluation of tumor thrombus level during sunitinib therapy for renal cell carcinoma.

    PubMed

    Sano, Futoshi; Fusayasu, Syusei; Otake, Shinji; Yamanaka, Hiroyuki; Tatenuma, Tomoyuki; Sakata, Ryoko; Makiyama, Kazuhide; Nakaigawa, Noboru; Yao, Masahiro; Kubota, Yoshinobu

    2013-10-01

    A 72-year-old man presenting with a 14-cm left renal mass, an inferior vena cava (IVC) tumor thrombus, and pulmonary metastases underwent renal mass biopsy that revealed clear cell renal cell carcinoma. Because of metastases and the extent of the tumor thrombus, sunitinib was administered, which resulted in a marked reduction in the tumor thrombus (from level III to level II after 11 weeks of treatment). Ultrasonography, preceding computed tomography, showed a slight shrinkage of the tumor thrombus level in the first 2 weeks. Therefore, ultrasound may be advantageous to monitor the IVC tumor thrombus level during the early phase of targeted therapy.

  12. Early detection, aggressive therapy: optimizing the management of feline mammary masses.

    PubMed

    Giménez, Fernanda; Hecht, Silke; Craig, Linden E; Legendre, Alfred M

    2010-03-01

    This article reviews the incidence, etiology, diagnosis, treatment and prognosis of mammary tumors in cats. Approximately 80% of feline mammary masses are malignant, with adenocarcinoma being the most common tumor type. Early diagnosis is, therefore, essential to improve the prognosis and quality of life of affected cats. Surgery is the most widely used treatment for malignant tumors. However, as mammary tumors are often advanced and metastasis has already occurred by the time of diagnosis, surgery routinely does not provide a cure. Ovariohysterectomy or hormonal therapy are the treatments of choice for fibroadenomatous hyperplasia (the most common benign mass) and usually lead to a successful outcome. Copyright 2010. Published by Elsevier Ltd.

  13. [The new concept of osteoporosis. Early diagnosis, prevention and therapy are possible today].

    PubMed

    Hesch, R D; Harms, H; Rittinghaus, E F; Brabant, G

    1990-04-15

    A paradigma of osteoporosis pathology is discussed, at the center of which is the hormone-related disturbance of the osteoblast/osteoclast functional unit. A liberal replacement of estrogen-gestagen in post-menopausal women is advocated. Early diagnosis with the aid of quantitative computed tomography makes it possible to establish the indication for timely hormonal treatment in the future, which can result in a measureable increase in bone mass. Late therapy, that is, treatment initiated after the occurrence of fractures, has proven largely ineffective.

  14. Impact of early initiation of corticosteroid therapy on cardiac function and rhythm in patients with cardiac sarcoidosis.

    PubMed

    Padala, Santosh K; Peaslee, Samuel; Sidhu, Mandeep S; Steckman, David A; Judson, Marc A

    2017-01-15

    There is limited data on the effect of corticosteroid therapy in patients with cardiac sarcoidosis (CS). We sought to examine the impact of early initiation of corticosteroid therapy, within a month of CS diagnosis, on left ventricular ejection fraction (LVEF), ventricular arrhythmias (VAs), and atrioventricular (AV) block. We retrospectively identified 30 CS patients from a large university sarcoidosis clinic. The effect of early initiation of corticosteroid therapy on LVEF was assessed by serial echocardiography, and on VAs and AV block was assessed by Holter monitoring and/or device interrogations. The median time from diagnosis of extra-cardiac sarcoidosis to CS was 40months. 90% (27/30) of the CS patients received corticosteroid therapy and 85% percent (23/27) had early initiation of corticosteroid therapy. Fourteen patients (47%) had reduced EF<50%. 9/14 patients who had early initiation of corticosteroid therapy had improvement in mean EF (25% to 46%, P<0.001); 5/14 patients who had a delay in initiation or who did not receive corticosteroids had no improvement in mean EF (41% to 37%, P=0.47). Fourteen patients (47%) had VAs and 5 patients (17%) had advanced AV block. Early initiation of corticosteroid therapy resulted in no VA recurrences in 8/11 patients (72%), and complete recovery of AV conduction in 2/3 patients (67%). Patients with VAs (n=3) or advanced AV block (n=2) who failed to receive early corticosteroid therapy did not show improvement. There is often a delay in manifestation of cardiac sarcoidosis for several years from the diagnosis of extra-cardiac sarcoidosis. Prompt initiation of corticosteroid therapy in CS patients may improve outcomes whereas delayed initiation of corticosteroids or failure to use corticosteroids may be associated with worse outcomes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy

    PubMed Central

    Whitmore, S.Scott; Sohn, Elliott H.; Chirco, Kathleen R.; Drack, Arlene V.; Stone, Edwin M.; Tucker, Budd A.; Mullins, Robert F.

    2015-01-01

    Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and biochemical data that indicate that vascular loss in the choroid occurs very early in the pathogenesis of AMD, and discuss the potential impact of vascular dropout on the retinal pigment epithelium, Bruch's membrane and the photoreceptor cells. Finally, we present a hypothesis for the pathogenesis of early AMD and consider the implications of this model on the development of new therapies. PMID:25486088

  16. Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy.

    PubMed

    Whitmore, S Scott; Sohn, Elliott H; Chirco, Kathleen R; Drack, Arlene V; Stone, Edwin M; Tucker, Budd A; Mullins, Robert F

    2015-03-01

    Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and biochemical data that indicate that vascular loss in the choroid occurs very early in the pathogenesis of AMD, and discuss the potential impact of vascular dropout on the retinal pigment epithelium, Bruch's membrane and the photoreceptor cells. Finally, we present a hypothesis for the pathogenesis of early AMD and consider the implications of this model on the development of new therapies. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Emerging Cardiac Imaging Modalities for the Early Detection of Cardiotoxicity Due to Anticancer Therapies.

    PubMed

    López-Fernández, Teresa; Thavendiranathan, Paaladinesh

    2017-06-01

    The undeniable advances in the field of oncology have finally led to a decrease in overall cancer-related mortality. However, this population of long-term cancer survivors is now facing a shift toward a substantial increase in cardiovascular morbidity and mortality. Because the development of overt cardiotoxicity can be associated with poor outcomes, preclinical identification of cardiac toxicity is important. This will promote early instauration of treatments to prevent overt heart dysfunction and allow oncologists to continue cancer therapy in an uninterrupted manner. Surveillance strategies for the early detection of cardiac injury include cardiac imaging and biomarkers during treatment. In this review, we outline existing cardiac imaging modalities to detect myocardial changes in patients undergoing cancer treatment and in survivors, and their strengths and limitations. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  18. Developing Singing Confidence in Early Childhood Teachers Using Acceptance and Commitment Therapy and Group Singing: A Randomized Trial

    ERIC Educational Resources Information Center

    Swain, Nicola; Bodkin-Allen, Sally

    2017-01-01

    Early childhood teachers are often required to sing, which requires confidence. The purpose of the present study was to treat early childhood teachers who self-identified as uncertain singers using either a group singing (GS) approach, or a talking approach, based on Acceptance and Commitment Therapy (ACT). The aim of the study was to increase…

  19. Negative affective spillover from daily events predicts early response to cognitive therapy for depression.

    PubMed

    Cohen, Lawrence H; Gunthert, Kathleen C; Butler, Andrew C; Parrish, Brendt P; Wenze, Susan J; Beck, Judith S

    2008-12-01

    This study evaluated the predictive role of depressed outpatients' (N = 62) affective reactivity to daily stressors in their rates of improvement in cognitive therapy (CT). For 1 week before treatment, patients completed nightly electronic diaries that assessed daily stressors and negative affect (NA). The authors used multilevel modeling to compute each patient's within-day relationship between daily stressors and daily NA (within-day reactivity), as well as the relationship between daily stressors and next-day NA (next-day reactivity; affective spillover). In growth model analyses, the authors evaluated the predictive role of patients' NA reactivity in their early (Sessions 1-4) and late (Sessions 5-12) response to CT. Within-day NA reactivity did not predict early or late response to CT. However, next-day reactivity predicted early response to CT, such that patients who had greater NA spillover in response to negative events had a slower rate of symptom change during the first 4 sessions. Affective spillover did not influence later response to CT. The findings suggest that depressed patients who have difficulty bouncing back the next day from their NA reactions to a relative increase in daily negative events will respond less quickly to the early sessions of CT.

  20. Antiviral active peptide from oyster

    NASA Astrophysics Data System (ADS)

    Zeng, Mingyong; Cui, Wenxuan; Zhao, Yuanhui; Liu, Zunying; Dong, Shiyuan; Guo, Yao

    2008-08-01

    An active peptide against herpes virus was isolated from the enzymic hydrolysate of oyster ( Crassostrea gigas) and purified with the definite direction hydrolysis technique in the order of alcalase and bromelin. The hydrolysate was fractioned into four ranges of molecular weight (>10 kDa, 10 5 kDa, 5 1 kDa and <1 kDa) using ultrafiltration membranes and dialysis. The fraction of 10 5 kDa was purified using consecutive chromatographic methods including DEAE Sephadex A-25 column, Sephadex G-25 column, and high performance liquid chromatogram (HPLC) by activity-guided isolation. The antiviral effect of the obtained peptide on herpetic virus was investigated in Vero cells by observing cytopathic effect (CPE). The result shows that the peptide has high inhibitory activity on herpetic virus.

  1. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause

    PubMed Central

    Sullivan, Shannon D.; Sarrel, Philip M.; Nelson, Lawrence M.

    2016-01-01

    Primary ovarian insufficiency (POI) is a rare but important cause of ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychological impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy to replace premenopausal levels of ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective hormone replacement therapy options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal ovarian hormone production and continuing HRT until the normal age of natural menopause, ~50 years. We address special populations of women with POI, including women with Turner Syndrome, women with increased risk of breast or ovarian cancer, women approaching the age of natural menopause, and breastfeeding women. PMID:27912889

  2. Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of chemoradiation therapy outcomes

    NASA Astrophysics Data System (ADS)

    Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Kumar, Sameera; Shang, Yu; Huang, Chong; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

    2016-08-01

    This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs‧) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.

  3. Developments in early diagnosis and therapy of HIV infection in newborns.

    PubMed

    Canals, Francisco; Masiá, Mar; Gutiérrez, Félix

    2018-01-01

    Infants who acquire HIV have an exceptionally high risk of morbidity and mortality if they do not receive antiretroviral therapy (ART). Areas covered: This review aims to summarize the currently available evidence on ART in HIV-infected neonates. Data were obtained from literature searches from PubMed, abstracts from International Conferences (2000-2017), and authors' files. Expert opinion: Current evidence favors early diagnosis and prompt ART of HIV infection in newborns. The precise timing of initiation of ART remains undetermined. Very early (close to birth) ART appears to limit the size of the viral reservoir and may restrict replication-competent virus, but the clinical benefit remains unproven. Among the current options for initial therapy, in full term neonates from 2 weeks of life onwards, a lopinavir/ritonavir-based three-drug regimen is preferred. In term infants, younger than 2 weeks a nevirapine-based regimen is recommended, although there are no clinical trial data supporting that initiating treatment before 2 weeks improves outcome compared to starting afterwards. Existing safety information is insufficient to recommend ART in preterm infants, with pharmacokinetic data available for zidovudine only. If ART is considered in this setting, an individual case assessment of the risk/benefit ratio of treatment should be made.

  4. [Early interventional group therapy for patients with incipient Alzheimer disease and their relatives].

    PubMed

    Scheurich, Armin; Schanz, Benno; Müller, Matthias J; Fellgiebel, Andreas

    2008-06-01

    Pilot study on an early-interventional group therapy for patients with incipient Alzheimer disease and their relatives. The present study investigates whether scientific progress in terms of earlier time of diagnostic certainty can be used for psychoeducation, maintenance of positive activities and prevention of comorbid depressive episodes. 12 patients (66.8 +/- 5.8 years, MMSE 24.0 +/- 4.0) together with 12 relatives have been treated with a bi-weekly group therapy program. For the patients treatment resulted in reduced anxiety, anergia and withdrawal, for their relatives reduced sleep disturbances, irascibility, and aggressiveness have been found. Only one of the patients suffered from a depressive episode. All participants expressed positive feedback and a high level of quality of life. By the straightforward psychosocial intervention it seems possible to use the earlier time of diagnostic certainty for early diagnosed patients suffering from incipient Alzheimer disease. However, results have to be replicated by a controlled, prospective study with larger sample sizes.

  5. Diffuse optical measurements of head and neck tumor hemodynamics for early prediction of chemoradiation therapy outcomes

    PubMed Central

    Dong, Lixin; Kudrimoti, Mahesh; Irwin, Daniel; Chen, Li; Kumar, Sameera; Shang, Yu; Huang, Chong; Johnson, Ellis L.; Stevens, Scott D.; Shelton, Brent J.; Yu, Guoqiang

    2016-01-01

    Abstract. This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs′) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96. PMID:27564315

  6. Predicting therapy outcome in patients with early and late obsessive-compulsive disorder (EOCD and LOCD).

    PubMed

    Langner, Judith; Laws, Manuela; Röper, Gisela; Zaudig, Michael; Hauke, Walter; Piesbergen, Christoph

    2009-10-01

    Increasing attention has been given to subtyping OCD with respect to different clinical profiles, response to drug treatments, comorbidity and age of onset. There are a number of studies looking at predictors of treatment outcome in OCD, but so far not for OCD subtypes. Prediction of outcome after cognitive-behavioural therapy was evaluated in 63 inpatients with early obsessive-compulsive disorder (EOCD < or = 12 years of age) and 191 patients with late obsessive-compulsive disorder (LOCD > 15 years of age). For EOCD patients factors predicting a good outcome included high motivation and high initial Y-BOCS scores. Factors associated with a bad outcome were higher age at assessment, a longer duration of psychiatric inpatient treatment before assessment and a low level of social functioning (BSS). For LOCD patients living in a stable relationship, high motivation and completing treatment predicted a favourable therapy outcome, while a low level of psychological functioning (BSS) and a longer duration of inpatient psychiatric treatment before assessment were associated with an undesirable therapy outcome. Subtyping OCD patients according to age of onset seems to be a promising avenue towards improving and developing more specified treatment programs.

  7. Effects of intensive therapy using gait trainer or floor walking exercises early after stroke.

    PubMed

    Peurala, Sinikka H; Airaksinen, Olavi; Huuskonen, Pirjo; Jäkälä, Pekka; Juhakoski, Mika; Sandell, Kaisa; Tarkka, Ina M; Sivenius, Juhani

    2009-02-01

    To analyse the effects of gait therapy for patients after acute stroke in a randomized controlled trial. Fifty-six patients with a mean of 8 days post-stroke participated in: (i) gait trainer exercise; (ii) walking training over ground; or (iii) conventional treatment. Patients in the gait trainer exercise and walking groups practiced gait for 15 sessions over 3 weeks and received additional physiotherapy. Functional Ambulatory Category and several secondary outcome measures assessing gait and mobility were administered before and after rehabilitation and at 6-month follow-up. Patients also evaluated their own effort. Walking ability improved more with intensive walk training compared with conventional treatment; median Functional Ambulatory Category was zero in all patients at the start of the study, but it was 3 in both walk-training groups and 0.5 in the conventional treatment group at the end of the therapy. Median Functional Ambulatory Category was 4 in both walk-training groups and 2.5 in conventional treatment group at 6-month follow-up. Mean accomplished walking distance was not different between the gait trainer exercise and over ground walking groups. Borg scale indicated more effort in over ground walking. Secondary outcomes also indicated improvements. Exercise therapy with walking training improved gait function irrespective of the method used, but the time and effort required to achieve the results favour the gait trainer exercise. Early intensive gait training resulted in better walking ability than did conventional treatment.

  8. [Analgesic effect of TES therapy in the early postoperative period in patients who underwent tonsillectomy].

    PubMed

    Semënov, F V; Kade, A Kh; Banashek-Meshchiarkova, T V; Vartanian, M S

    2013-01-01

    The objective of the present work was to study peculiarities of the analgesic action of therapeutic electrical stimulation (TES therapy) in the early postoperative period in the patients who underwent tonsillectomy. A total of 60 patients admitted for this surgery to the specialized otorhinolaryngological department were available for observation. They were divided into two groups depending on the pain relief strategy. The patients of the study group (n=30) underwent courses of transcranial electrical stimulation on a daily basis (from the onset of hospitalization) in addition to the administration of a standard analgetic. The standard dose of tramadol (2.0 ml) was given to the patients of the control group (n=30) who complained of strong pain. The results of the objective and subjective estimations indicate that the degree of pharyngeal pain in the patients treated with TES therapy and the standard analgetic was significantly different. The patients receiving TES therapy could sooner resume their habitual diet and required smaller amounts of the analgetic which makes this modality a cost-effective supplement to the standard postoperative treatment.

  9. An overview of experimental and early investigational therapies for the treatment of polycystic kidney disease.

    PubMed

    Santoro, Domenico; Pellicanò, Vincenzo; Visconti, Luca; Trifirò, Gianluca; Buemi, Michele; Cernaro, Valeria

    2015-01-01

    At present, treatment of autosomal dominant polycystic kidney disease (ADPKD) is essentially supportive as there is still no specific therapy. However, recent advances with ADPKD pathophysiology have stimulated research for new therapeutic strategies. The aim of this systematic review is to analyze the experimental and early investigational therapies currently under evaluation in this field. Data from completed clinical trials were retrieved from the currently available scientific literature and from the ClinicalTrials.gov website. Among the drugs currently being explored, mammalian target of rapamycin inhibitors reduce kidney volume enlargement but their role remains uncertain. The most promising drug is the V2 receptor antagonist tolvaptan, which reduces the increased rate of total kidney volume and slows down glomerular filtration rate decline. The main candidates for the treatment of cysts growth, both in the kidney and in the liver whenever present, are the somatostatin analogues, such as lanreotide and octreotide and more recently pasireotide. As for other therapies, some favorable results have been achieved but data are still not sufficient to establish if these approaches may be beneficial in slowing ADPKD progression in the future.

  10. Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy.

    PubMed

    Honeyborne, Isobella; McHugh, Timothy D; Kuittinen, Iitu; Cichonska, Anna; Evangelopoulos, Dimitrios; Ronacher, Katharina; van Helden, Paul D; Gillespie, Stephen H; Fernandez-Reyes, Delmiro; Walzl, Gerhard; Rousu, Juho; Butcher, Philip D; Waddell, Simon J

    2016-04-07

    New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb m

  11. Economic and epidemiological impact of early antiretroviral therapy initiation in India

    PubMed Central

    Maddali, Manoj V; Dowdy, David W; Gupta, Amita; Shah, Maunank

    2015-01-01

    Introduction Recent WHO guidance advocates for early antiretroviral therapy (ART) initiation at higher CD4 counts to improve survival and reduce HIV transmission. We sought to quantify how the cost-effectiveness and epidemiological impact of early ART strategies in India are affected by attrition throughout the HIV care continuum. Methods We constructed a dynamic compartmental model replicating HIV transmission, disease progression and health system engagement among Indian adults. Our model of the Indian HIV epidemic compared implementation of early ART initiation (i.e. initiation above CD4 ≥350 cells/mm3) with delayed initiation at CD4 ≤350 cells/mm3; primary outcomes were incident cases, deaths, quality-adjusted-life-years (QALYs) and costs over 20 years. We assessed how costs and effects of early ART initiation were impacted by suboptimal engagement at each stage in the HIV care continuum. Results Assuming “idealistic” engagement in HIV care, early ART initiation is highly cost-effective ($442/QALY-gained) compared to delayed initiation at CD4 ≤350 cells/mm3 and could reduce new HIV infections to <15,000 per year within 20 years. However, when accounting for realistic gaps in care, early ART initiation loses nearly half of potential epidemiological benefits and is less cost-effective ($530/QALY-gained). We project 1,285,000 new HIV infections and 973,000 AIDS-related deaths with deferred ART initiation with current levels of care-engagement in India. Early ART initiation in this continuum resulted in 1,050,000 new HIV infections and 883,000 AIDS-related deaths, or 18% and 9% reductions (respectively), compared to current guidelines. Strengthening HIV screening increases benefits of earlier treatment modestly (1,001,000 new infections; 22% reduction), while improving retention in care has a larger modulatory impact (676,000 new infections; 47% reduction). Conclusions Early ART initiation is highly cost-effective in India but only has modest

  12. Past, present and future of cyanide antagonism research: From the early remedies to the current therapies.

    PubMed

    Petrikovics, Ilona; Budai, Marianna; Kovacs, Kristof; Thompson, David E

    2015-06-26

    This paper reviews milestones in antidotal therapies for cyanide (CN) spanning early remedies, current antidotal systems and research towards next generation therapies. CN has been a part of plant defense mechanisms for millions of years. It became industrially important in the nineteenth century with the advent of CN assisted gold mining and the use of CN as a pest control agent. The biochemical basis of CN poisoning was actively studied and key mechanisms were understood as early as 1929. These fundamental studies led to a variety of antidotes, including indirect CN binders that generate methemoglobin, direct CN binders such as hydroxocobalamin, and sulfur donors that convert CN to the less toxic thiocyanate. Research on blood gases at the end of the twentieth century shed new light on the role of nitric oxide (NO) in the body. The discovery of NO's ability to compete with CN for enzymatic binding sites provided a previously missed explanation for the rapid efficacy of NO generating antidotes such as the nitrites. Presently used CN therapies include: methemoglobin/NO generators (e.g., sodium nitrite, amyl nitrite, and dimethyl aminophenol), sulfur donors (e.g., sodium thiosulfate and glutathione), and direct binding agents [(e.g., hydroxocobalamin and dicobalt salt of ethylenediaminetetraacetic acid (dicobalt edetate)]. A strong effort is being made to explore novel antidotal systems and to formulate them for rapid administration at the point of intoxication in mass casualty scenarios. New antidotes, formulations, and delivery systems are enhancing bioavailability and efficacy and hold promise for a new generation of improved CN countermeasures.

  13. A randomised controlled trial of occupational therapy for people with early rheumatoid arthritis.

    PubMed

    Hammond, A; Young, A; Kidao, R

    2004-01-01

    Occupational therapy (OT) aims at improving performance of daily living tasks, facilitating successful adjustments in lifestyle, and preventing losses of function. To evaluate the effects of a pragmatic, comprehensive OT programme on self management and health status of people with early rheumatoid arthritis (RA) (<2.5 years). A randomised, controlled "assessor blinded" trial was conducted with assessments made at entry, 6, 12, and 24 months. Main outcomes were AIMS2: physical function (PF), pain visual analogue scale (VAS), and Arthritis Self-Efficacy Scale (ASES). Groups had similar disease duration (9 months OT (n = 162) v 10 months control (n = 164)). The OT group received 7.57 (SD 3.04) hours of therapy. Self management significantly increased in the OT group. Otherwise, there were no significant differences in any outcome measures, or between groups, by ACR functional class: AIMS2: PF (F = 0.04; p = 0.96); pain VAS (F = 0.29; p = 0.74); total ASES score (F = 0.93; p = 0.39). OT improved self management but not health status in early RA. Functional ability remains reasonably good for many in the first five years, so preventive benefits of self management may not yet be apparent and longer follow up is needed. Although many considered the education and therapy useful, insufficient numbers in the OT group used self management sufficiently to make a difference. Behavioural approaches can improve adherence and, potentially, the long term benefits. Future research should evaluate OT as a complex intervention and develop programmes from a theoretical and evidence base.

  14. Prognostic factors for patients with early-stage uterine serous carcinoma without adjuvant therapy.

    PubMed

    Tate, Keisei; Yoshida, Hiroshi; Ishikawa, Mitsuya; Uehara, Takashi; Ikeda, Shun Ichi; Hiraoka, Nobuyoshi; Kato, Tomoyasu

    2018-05-01

    Uterine serous carcinoma (USC) is an aggressive type 2 endometrial cancer. Data on prognostic factors for patients with early-stage USC without adjuvant therapy are limited. This study aims to assess the baseline recurrence risk of early-stage USC patients without adjuvant treatment and to identify prognostic factors and patients who need adjuvant therapy. Sixty-eight patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-II USC between 1997 and 2016 were included. All the cases did not undergo adjuvant treatment as institutional practice. Clinicopathological features, recurrence patterns, and survival outcomes were analyzed to determine prognostic factors. FIGO stages IA, IB, and II were observed in 42, 7, and 19 cases, respectively. Median follow-up time was 60 months. Five-year disease-free survival (DFS) and overall survival (OS) rates for all cases were 73.9% and 78.0%, respectively. On multivariate analysis, cervical stromal involvement and positive pelvic cytology were significant predictors of DFS and OS, and ≥1/2 myometrial invasion was also a significant predictor of OS. Of 68 patients, 38 patients had no cervical stromal invasion or positive pelvic cytology and showed 88.8% 5-year DFS and 93.6% 5-year OS. Cervical stromal invasion and positive pelvic cytology are prognostic factors for stage I-II USC. Patients with stage IA or IB USC showing negative pelvic cytology may have an extremely favorable prognosis and need not receive any adjuvant therapies. Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

  15. Predictive Value of Early Skin Rash in Cetuximab-Based Therapy of Advanced Biliary Tract Cancer.

    PubMed

    Rubovszky, Gábor; Budai, Barna; Ganofszky, Erna; Horváth, Zsolt; Juhos, Éva; Madaras, Balázs; Nagy, Tünde; Szabó, Eszter; Pintér, Tamás; Tóth, Erika; Nagy, Péter; Láng, István; Hitre, Erika

    2018-04-01

    Randomized trials in advanced biliary tract cancer (BTC) did not show benefit of cetuximab addition over chemotherapy. This is probably due to the lack of predictive biomarkers. The aim of this study was to explore possible predictive factors. Between 2009 and 2014, 57 patients were treated in 3-week cycles with cetuximab (250 mg/m 2 /week, loading dose: 400 mg/m 2 ), gemcitabine (1000 mg/m 2 on day 1 and 8), and capecitabine (1300 mg/m 2 /day on days 1-14). The objective response rate (ORR), progression-free (PFS) and overall survival (OS) and the adverse events (AEs) were evaluated. An exploratory analysis was performed to find possible predictive factors on clinicopathological characteristics, routine laboratory parameters and early AEs, which occurred within 2 months from the beginning of treatment. The ORR was 21%. The median PFS and OS were 34 (95% CI: 24-40) and 54 (43-67) weeks, respectively. The most frequent AEs were skin toxicities. In univariate analysis performance status, previous stent implantation, thrombocyte count at the start of therapy, early neutropenia and skin rash statistically significantly influenced the ORR, PFS and/or OS. In multivariate Cox regression analysis only normal thrombocyte count at treatment start and early acneiform rash were independent markers of longer survival. In patients showing early skin rash compared to the others the median PFS was 39 vs. 13 weeks and the median OS was 67 vs. 26 weeks, respectively. It is suggested that early skin rash can be used as a biomarker to select patients who would benefit from the treatment with cetuximab plus chemotherapy.

  16. Antiviral activity of lanatoside C against dengue virus infection.

    PubMed

    Cheung, Yan Yi; Chen, Karen Caiyun; Chen, Huixin; Seng, Eng Khuan; Chu, Justin Jang Hann

    2014-11-01

    Dengue infection poses a serious threat globally due to its recent rapid spread and rise in incidence. Currently, there is no approved vaccine or effective antiviral drug for dengue virus infection. In response to the urgent need for the development of an effective antiviral for dengue virus, the US Drug Collection library was screened in this study to identify compounds with anti-dengue activities. Lanatoside C, an FDA approved cardiac glycoside was identified as a candidate anti-dengue compound. Our data revealed that lanatoside C has an IC50 of 0.19μM for dengue virus infection in HuH-7 cells. Dose-dependent reduction in dengue viral RNA and viral proteins synthesis were also observed upon treatment with increasing concentrations of lanatoside C. Time of addition study indicated that lanatoside C inhibits the early processes of the dengue virus replication cycle. Furthermore, lanatoside C can effectively inhibit all four serotypes of dengue virus, flavivirus Kunjin, alphavirus Chikungunya and Sindbis virus as well as the human enterovirus 71. These findings suggest that lanatoside C possesses broad spectrum antiviral activity against several groups of positive-sense RNA viruses. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Antiviral activity of lauryl gallate against animal viruses.

    PubMed

    Hurtado, Carolina; Bustos, Maria Jose; Sabina, Prado; Nogal, Maria Luisa; Granja, Aitor G; González, Maria Eugenia; Gónzalez-Porqué, Pedro; Revilla, Yolanda; Carrascosa, Angel L

    2008-01-01

    Antiviral compounds are needed in the control of many animal and human diseases. We analysed the effect of the antitumoural drug lauryl gallate on the infectivity of the African swine fever virus among other DNA (herpes simplex and vaccinia) and RNA (influenza, porcine transmissible gastroenteritis and Sindbis) viruses, paying attention to its effect on the viability of the corresponding host cells. Viral production was strongly inhibited in different cell lines at non-toxic concentrations of the drug (1-10 microM), reducing the titres 3->5 log units depending on the multiplicity of infection. In our model system (African swine fever virus in Vero cells), the addition of the drug 1 h before virus adsorption completely abolished virus productivity in a one-step growth virus cycle. Interestingly, no inhibitory effect was observed when lauryl gallate was added after 5-8 h post-infection. Both cellular and viral DNA synthesis and late viral transcription were inhibited by the drug; however, the early viral protein synthesis and the virus-mediated increase of p53 remained unaffected. Activation of the apoptotic effector caspase-3 was not detected after lauryl gallate treatment of Vero cells. Furthermore, the presence of the drug abrogated the activation of this protease induced by the virus infection. Lauryl gallate is a powerful antiviral agent against several pathogens of clinical and veterinary importance. The overall results indicate that a cellular factor or function might be the target of the antiviral action of alkyl gallates.

  18. Antiviral agents and HIV prevention: controversies, conflicts, and consensus

    PubMed Central

    Cohen, Myron S.; Muessig, Kathryn E.; Smith, M. Kumi; Powers, Kimberly A.; Kashuba, Angela D.M.

    2013-01-01

    Antiviral agents can be used to prevent HIV transmission before exposure as preexpo-sure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups – including intravenous drug users and MSM – has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation. PMID:22507927

  19. Low-Dose Consolidation Radiation Therapy for Early Stage Unfavorable Hodgkin Lymphoma

    SciTech Connect

    Torok, Jordan A., E-mail: jordan.torok@dm.duke.edu; Wu, Yuan; Prosnitz, Leonard R.

    Purpose: The German Hodgkin Study Group (GHSG) trial HD11 established 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and 30 Gy of radiation therapy (RT) as a standard for early stage (I, II), unfavorable Hodgkin lymphoma (HL). Additional cycles of ABVD may allow for a reduction in RT dose and improved toxicity profile. Methods and Materials: Patients treated with combined modality therapy at the Duke Cancer Institute for early stage, unfavorable HL by GHSG criteria from 1994 to 2012 were included. Patients who did not undergo post-chemotherapy functional imaging (positron emission tomography or gallium imaging) or who failed to achievemore » a complete response were excluded. Clinical outcomes were estimated using the Kaplan-Meier method. Late effects were also evaluated. Results: A total of 90 patients met inclusion criteria for analysis. Median follow-up was 5 years. Chemotherapy consisted primarily of ABVD (88%) with a median number of 6 cycles. The median dose of consolidation RT was 23.4 Gy. Four patients had relapses, 2 of which were in-field. Ten-year progression-free survival (PFS) and overall survival (OS) were 93% (95% confidence interval [CI]: 0.82-0.97) and 98% (95% CI: 0.92-0.99), respectively. For the subset of patients (n=46) who received 5 to 6 cycles of chemotherapy and ≤24 Gy, the 10-year PFS and OS values were 88% (95% CI: 70%-96%) and 98% (95% CI: 85% - 99%), respectively. The most common late effect was hypothyroidism (20%) with no cardiac complications. Seven secondary malignancies were diagnosed, with only 1 arising within the RT field. Conclusions: Lower doses of RT may be sufficient when combined with more than 4 cycles of ABVD for early stage, unfavorable HL and may result in a more favorable toxicity profile than 4 cycles of ABVD and 30 Gy of RT.« less

  20. Nucleic acid polymers: Broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection.

    PubMed

    Vaillant, Andrew

    2016-09-01

    Antiviral polymers are a well-studied class of broad spectrum viral attachment/entry inhibitors whose activity increases with polymer length and with increased amphipathic (hydrophobic) character. The newest members of this class of compounds are nucleic acid polymers whose activity is derived from the sequence independent properties of phosphorothioated oligonucleotides as amphipathic polymers. Although the antiviral mechanisms and broad spectrum antiviral activity of nucleic acid polymers mirror the functionality of other members of this class, they exert in addition a unique post entry activity in hepatitis B infection which inhibits the release of HBsAg from infected hepatocytes. This review provides a general overview of the antiviral polymer class with a focus on nucleic acid polymers and their development as therapeutic agents for the treatment of hepatitis B/hepatitis D. This article forms part of a symposium in Antiviral Research on ''An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.''. Copyright © 2016 The Author. Published by Elsevier B.V. All rights reserved.

  1. Addressing the selectivity and toxicity of antiviral nucleosides.

    PubMed

    Feng, Joy Y

    2018-01-01

    Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies.

  2. Recurrence of CMV Infection and the Effect of Prolonged Antivirals in Organ Transplant Recipients.

    PubMed

    Natori, Yoichiro; Humar, Atul; Husain, Shahid; Rotstein, Coleman; Renner, Eberhard; Singer, Lianne; Kim, S Joseph; Kumar, Deepali

    2017-06-01

    Although initial therapy for cytomegalovirus (CMV) is usually successful, a significant subset of patients may have recurrent viremia. However, the epidemiology and risk factors for recurrence have not been fully defined, as well as the utility of prolonged antivirals after initial clearance. Solid organ transplant patients with first episode of CMV disease or asymptomatic viremia (≥1000 IU/mL) requiring treatment were identified by chart review. Clinical and virologic data were collected. The primary outcome was recurrence of CMV viremia or disease within 6 months of treatment discontinuation. The first episode of CMV viremia requiring antiviral therapy was assessed in 282 patients (147 CMV disease and 135 asymptomatic viremia). Cytomegalovirus occurred at 5.6 (0.63-27.7) months posttransplant. Recurrent CMV occurred in 30.5% patients at a median of 51 (0-160) days after discontinuation of therapy. Factors predictive of recurrence were treatment phase viral kinetics (P = 0.005), lung transplant (P = 0.002), CMV donor (D)+/recipient (R)- serostatus(P = 0.04) and recent acute rejection(P = 0.02). Prolonged antiviral therapy was given to 226 (80.1%) of 282 patients. Recurrence occurred in 73 (32.3%) of 226 patients that received prolonged antivirals versus 13 (23.2%) of 56 in those with no prolonged antivirals (P = 0.19). Recurrent CMV occurs in a significant percentage of patients after treatment of the first episode of CMV viremia/disease. CMV D+/R- serostatus, lung transplant, and treatment phase viral kinetics were significant predictors of recurrence. Continuation of prolonged antivirals beyond initial clearance was not associated with a reduced risk of recurrence.

  3. Assessment of Inhibition of Ebola Virus Progeny Production by Antiviral Compounds.

    PubMed

    Falzarano, Darryl

    2017-01-01

    Assessment of small molecule compounds against filoviruses, such as Ebola virus, has identified numerous compounds that appear to have antiviral activity and should presumably be further investigated in animal efficacy trials. However, despite the many compounds that are purported to have good antiviral activity in in vitro studies, there are few instances where any efficacy has been reported in nonhuman primate models. Many of the high-throughput screening assays use reporter systems that only recapitulate a portion of the virus life cycle, while other assays only assess antiviral activity at relatively early time points. Moreover, many assays do not assess virus progeny production. A more in-depth evaluation of small numbers of test compounds is useful to economize resources and to generate higher quality antiviral hits. Assessing virus progeny production as late as 5 days post-infection allows for the elimination of compounds that have initial antiviral effects that are not sustained or where the virus rapidly develops resistance. While this eliminates many potential lead compounds that may be worthy of further structure-activity relationship (SAR) development, it also quickly excludes compounds that in their current form are unlikely to be effective in animal models. In addition, the inclusion of multiple assays that assess both cell viability and cell cytotoxicity, via different mechanisms, provides a more thorough assessment to exclude compounds that are not direct-acting antivirals.

  4. Risk of Fatal Cerebrovascular Accidents after External Beam Radiation Therapy for Early Stage Glottic Larynx Cancer

    PubMed Central

    Swisher-McClure, Samuel; Mitra, Nandita; Lin, Alexander; Ahn, Peter; Wan, Fei; O’Malley, Bert; Weinstein, Gregory S.; Bekelman, Justin E.

    2013-01-01

    Background This study compared the risk of fatal cerebrovascular accidents (CVA) in patients with early stage glottic larynx cancer receiving surgery or external beam radiation therapy (EBRT). Methods and Materials Using a competing risks survival analysis, we compared the risk of death due to CVA among patients with early stage glottic larynx cancer receiving surgery or EBRT in the SEER database. Results The cumulative incidence of fatal CVA at 15 years was higher in patients receiving EBRT (2.8 %; 95% CI 2.3%–3.4%) compared to surgery (1.5 %; 95% CI 0.8 %–2.3%, p= 0.024). In multivariable competing risks regression models, EBRT remained associated with an increased risk of fatal CVA compared to surgery (adjusted HR 1.75; 95% CI 1.04–2.96, p= 0.037). Conclusion Treatment of early stage glottic larynx cancer with EBRT was associated with a small increase in the risk of late fatal CVA events relative to surgery. PMID:23595858

  5. Accelerated Partial Breast Irradiation Using Only Intraoperative Electron Radiation Therapy in Early Stage Breast Cancer

    SciTech Connect

    Maluta, Sergio; Dall'Oglio, Stefano, E-mail: stefano.dalloglio@ospedaleuniverona.it; Marciai, Nadia

    2012-10-01

    Background: We report the results of a single-institution, phase II trial of accelerated partial breast irradiation (APBI) using a single dose of intraoperative electron radiation therapy (IOERT) in patients with low-risk early stage breast cancer. Methods and Materials: A cohort of 226 patients with low-risk, early stage breast cancer were treated with local excision and axillary management (sentinel node biopsy with or without axillary node dissection). After the surgeon temporarily reapproximated the excision cavity, a dose of 21 Gy using IOERT was delivered to the tumor bed, with a margin of 2 cm laterally. Results: With a mean follow-up ofmore » 46 months (range, 28-63 months), only 1 case of local recurrence was reported. The observed toxicity was considered acceptable. Conclusions: APBI using a single dose of IOERT can be delivered safely in women with early, low-risk breast cancer in carefully selected patients. A longer follow-up is needed to ascertain its efficacy compared to that of the current standard treatment of whole-breast irradiation.« less

  6. Proton Therapy for Craniopharyngioma - An Early Report from a Single European Centre.

    PubMed

    Ajithkumar, T; Mazhari, A-L; Stickan-Verfürth, M; Kramer, P-H; Fuentes, C-S; Lambert, J; Thomas, H; Müller, H; Fleischhack, G; Timmermann, B

    2018-05-01

    Proton beam therapy (PBT) is being increasingly used for craniopharyngioma. We describe our early outcome of patients treated with PBT. Between August 2013 and July 2016, 18 patients with craniopharyngiomas were treated with 54 Cobalt Gray Equivalent (CGE) in 30 fractions over 6 weeks at our centre. The early outcome of 16 patients included in a registry study was analysed. Radiological response was assessed by RECIST criteria and the disease- and treatment-related toxicities were scored according to the CTCAE 4.0. All patients are alive at a median follow-up of 32.6 months (range 9.2-70.6 months) from initial diagnosis. The median age at PBT was 10.2 years (range 5.4-46.9 years). One patient progressed 8.7 months after PBT and subsequently had complete resection of the tumour. At a median follow-up of 18.4 months after PBT, five patients remained in complete remission, four in partial remission and seven with stable disease. The most common adverse effects during PBT were grade 1 (cutaneous in seven patients and fatigue in six patients). There were no treatment-related grade 3 toxicities. Our early results are encouraging and comparable with the limited literature on PBT for craniopharyngioma. Copyright © 2018. Published by Elsevier Ltd.

  7. MicroRNAs as biomarkers for early breast cancer diagnosis, prognosis and therapy prediction.

    PubMed

    Nassar, Farah J; Nasr, Rihab; Talhouk, Rabih

    2017-04-01

    Breast cancer is a major health problem that affects one in eight women worldwide. As such, detecting breast cancer at an early stage anticipates better disease outcome and prolonged patient survival. Extensive research has shown that microRNA (miRNA) are dysregulated at all stages of breast cancer. miRNA are a class of small noncoding RNA molecules that can modulate gene expression and are easily accessible and quantifiable. This review highlights miRNA as diagnostic, prognostic and therapy predictive biomarkers for early breast cancer with an emphasis on the latter. It also examines the challenges that lie ahead in their use as biomarkers. Noteworthy, this review addresses miRNAs reported in patients with early breast cancer prior to chemotherapy, radiotherapy, surgical procedures or distant metastasis (unless indicated otherwise). In this context, miRNA that are mentioned in this review were significantly modulated using more than one statistical test and/or validated by at least two studies. A standardized protocol for miRNA assessment is proposed starting from sample collection to data analysis that ensures comparative analysis of data and reproducibility of results. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Herpes Zoster reactivation in patients with chronic hepatitis C under treatment with directly acting antiviral agents: A case series.

    PubMed

    El Kassas, Mohamed; Wifi, Mohamed Naguib; Mahdy, Reem; Afify, Shimaa; Hafez, Enas; El Latif, Yasmeen Abd; Ezzat, Marwa; El Tahan, Adel; Youssef, Naglaa; Esmat, Gamal

    2017-03-01

    We report a series of cutaneous Herpes Zoster (HZ) reactivation cases in patients with hepatitis C virus (HCV) infection treated with directly acting antiviral (DAA) agents. Five cases were detected among 2133 treated patients with DAAs at one of the specialized viral hepatitis treatment centers in Egypt. A control group including 2300 age and sex matched HCV patients who were previously treated with pegylated interferon and ribavirin did not show any HZ reactivation reports while on treatment. None of cases had an evidence of immunosuppression or a risk factor for HZ reactivation. The DAAs used regimens were sofosbuvir/daclatasvir in 4 cases and sofosbuvir/simeprevir in one case. HCV clearance with antiviral therapy may bring immune changes causing reactivation of other latent viral infections like HZ. A high index of clinical suspicion may be needed to guarantee early and prompt management of such cases. Copyright © 2017 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.

  9. Early mortality among children and adults in antiretroviral therapy programs in Southwest Ethiopia, 2003-15.

    PubMed

    Gesesew, Hailay Abrha; Ward, Paul; Woldemichael, Kifle; Mwanri, Lillian

    2018-01-01

    Several studies reported that the majority of deaths in HIV-infected people are documented in their early antiretroviral therapy (ART) follow-ups. Early mortality refers to death of people on ART for follow up period of below 24 months due to any cause. The current study assessed predictors of early HIV mortality in Southwest Ethiopia. We have conducted a retrospective analysis of 5299 patient records dating from June 2003- March 2015. To estimate survival time and compare the time to event among the different groups of patients, we used a Kaplan Meir curve and log-rank test. To identify mortality predictors, we used a cox regression analysis. We used SPSS-20 for all analyses. A total of 326 patients died in the 12 years follow-up period contributing to 6.2% cumulative incidence and 21.7 deaths per 1000 person-year observations incidence rate. Eighty-nine percent of the total deaths were documented in the first two years follow up-an early-term ART follow up. Early HIV mortality rates among adults were 50% less in separated, divorced or widowed patients compared with never married patients, 1.6 times higher in patients with baseline CD4 count <200 cells/μL compared to baseline CD4 count ≥200 cells/μL, 1.5 times higher in patients with baseline WHO clinical stage 3 or 4 compared to baseline WHO clinical stage 1 or 2, 2.1 times higher in patients with immunologic failure compared with no immunologic failure, 60% less in patients with fair or poor compared with good adherence, 2.9 times higher in patients with bedridden functional status compared to working functional status, and 2.7 times higher with patients who had no history of HIV testing before diagnosis compared to those who had history of HIV testing. Most predictors of early mortality remained the same to the predictors of an overall HIV mortality. When discontinuation was assumed as an event, the predictors of an overall HIV mortality included age between 25-50 years, base line CD4 count, developing

  10. Cost-Effectiveness of Early Versus Standard Antiretroviral Therapy in HIV-Infected Adults in Haiti

    PubMed Central

    Koenig, Serena P.; Bang, Heejung; Severe, Patrice; Jean Juste, Marc Antoine; Ambroise, Alex; Edwards, Alison; Hippolyte, Jessica; Fitzgerald, Daniel W.; McGreevy, Jolion; Riviere, Cynthia; Marcelin, Serge; Secours, Rode; Johnson, Warren D.; Pape, Jean W.; Schackman, Bruce R.

    2011-01-01

    Background In a randomized clinical trial of early versus standard antiretroviral therapy (ART) in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, early ART decreased mortality by 75%. We assessed the cost-effectiveness of early versus standard ART in this trial. Methods and Findings Trial data included use of ART and other medications, laboratory tests, outpatient visits, radiographic studies, procedures, and hospital services. Medication, laboratory, radiograph, labor, and overhead costs were from the study clinic, and hospital and procedure costs were from local providers. We evaluated cost per year of life saved (YLS), including patient and caregiver costs, with a median of 21 months and maximum of 36 months of follow-up, and with costs and life expectancy discounted at 3% per annum. Between 2005 and 2008, 816 participants were enrolled and followed for a median of 21 months. Mean total costs per patient during the trial were US$1,381 for early ART and US$1,033 for standard ART. After excluding research-related laboratory tests without clinical benefit, costs were US$1,158 (early ART) and US$979 (standard ART). Early ART patients had higher mean costs for ART (US$398 versus US$81) but lower costs for non-ART medications, CD4 cell counts, clinically indicated tests, and radiographs (US$275 versus US$384). The cost-effectiveness ratio after a maximum of 3 years for early versus standard ART was US$3,975/YLS (95% CI US$2,129/YLS–US$9,979/YLS) including research-related tests, and US$2,050/YLS excluding research-related tests (95% CI US$722/YLS–US$5,537/YLS). Conclusions Initiating ART in HIV-infected adults with a CD4 cell count between 200 and 350 cells/mm3 in Haiti, consistent with World Health Organization advice, was cost-effective (US$/YLS <3 times gross domestic product per capita) after a maximum of 3 years, after excluding research-related laboratory tests. Trial registration ClinicalTrials.gov NCT00120510 Please see

  11. Steroid/Antiviral for the treatment of Bell's palsy: Double blind randomized clinical trial.

    PubMed

    Khedr, Eman Mohamed; Badry, Reda; Ali, Anwer Mohamed; Abo El-Fetoh, Noha; El-Hammady, Dina Hatem; Ghandour, Abeer Mohamed; Abdel-Haleem, Ahmed

    2016-11-22

    A large number of patients with Bell's palsy fail to recover facial function completely after steroid therapy. Only a few small trials have been conducted to test whether outcomes can be improved by the addition of antiviral therapy. To evaluate the efficacy of treatment with steroid alone versus steroid + antiviral in a group of patients with moderately severe to severe acute Bell's palsy. Fifty eligible patients out of a total of 65 with acute onset Bell's palsy were randomized to receive the two treatments. Evaluation was performed before starting treatment, after 2 weeks of treatment and 3 months after onset, using the House and Brackmann facial nerve grading system (HB) and the Sunnybrook grading system.This study was registered with ClinicalTrials.gov, number NCT02328079. Both treatments had comparable demographics and clinical scores at baseline. There was greater improvement in the mean HB and Sunnybrook scores of the steroid + antiviral group in comparison to steroid group at 3 months. At the end of the 3rd month, 17 patients (68%) had good recovery and 8 patients (32%) had poor recovery in the steroid group compared with 23 patients (92%) and 2 (8%) respectively in the steroid and antiviral group (p = 0.034). The combination of steroid and antiviral treatment increases the possibility of recovery in moderately severe to complete acute Bell's palsy.

  12. Dosimetric comparison of hybrid volumetric-modulated arc therapy, volumetric-modulated arc therapy, and intensity-modulated radiation therapy for left-sided early breast cancer

    SciTech Connect

    Lin, Jia-Fu; Yeh, Dah-Cherng; Yeh, Hui-Ling, E-mail: hlyeh@vghtc.gov.tw

    2015-10-01

    To compare the dosimetric performance of 3 different treatment techniques: hybrid volumetric-modulated arc therapy (hybrid-VMAT), pure-VMAT, and fixed-field intensity-modulated radiation therapy (F-IMRT) for whole-breast irradiation of left-sided early breast cancer. The hybrid-VMAT treatment technique and 2 other treatment techniques—pure-VMAT and F-IMRT—were compared retrospectively in 10 patients with left-sided early breast cancer. The treatment plans of these patients were replanned using the same contours based on the original computed tomography (CT) data sets. Dosimetric parameters were calculated to evaluate plan quality. Total monitor units (MUs) and delivery time were also recorded and evaluated. The hybrid-VMAT plan generated the best results inmore » dose coverage of the target and the dose uniformity inside the target (p < 0.0001 for conformal index [CI]; p = 0.0002 for homogeneity index [HI] of planning target volume [PTV]{sub 50.4} {sub Gy} and p < 0.0001 for HI of PTV{sub 62} {sub Gy}). Volumes of ipsilateral lung irradiated to doses of 20 Gy (V{sub 20} {sub Gy}) and 5 Gy (V{sub 5} {sub Gy}) by the hybrid-VMAT plan were significantly less than those of the F-IMRT and the pure-VMAT plans. The volume of ipsilateral lung irradiated to a dose of 5 Gy was significantly less using the hybrid-VMAT plan than that using the F-IMRT or the pure-VMAT plan. The total mean MUs for the hybrid-VMAT plan were significantly less than those for the F-IMRT or the pure-VMAT plan. The mean machine delivery time was 3.23 ± 0.29 minutes for the hybrid-VMAT plans, which is longer than that for the pure-VMAT plans but shorter than that for the F-IMRT plans. The hybrid-VMAT plan is feasible for whole-breast irradiation of left-sided early breast cancer.« less

  13. The impact of early symptom change and therapeutic alliance on treatment outcome in cognitive-behavioural therapy for eating disorders.

    PubMed

    Turner, Hannah; Bryant-Waugh, Rachel; Marshall, Emily

    2015-10-01

    The present study explored the impact of early symptom change (cognitive and behavioural) and the early therapeutic alliance on treatment outcome in cognitive-behavioural therapy (CBT) for the eating disorders. Participants were 94 adults with diagnosed eating disorders who completed a course of CBT in an out-patient community eating disorders service in the UK. Patients completed a measure of eating disorder psychopathology at the start of treatment, following the 6th session and at the end of treatment. They also completed a measure of therapeutic alliance following the 6th session. Greater early reduction in dietary restraint and eating concerns, and smaller levels of change in shape concern, significantly predicted later reduction in global eating pathology. The early therapeutic alliance was strong across the three domains of tasks, goals and bond. Early symptom reduction was a stronger predictor of later reduction in eating pathology than early therapeutic alliance. The early therapeutic alliance did not mediate the relationship between early symptom reduction and later reduction in global eating pathology. Instead, greater early symptom reduction predicted a strong early therapeutic alliance. Early clinical change was the strongest predictor of treatment outcome and this also facilitated the development of a strong early alliance. Clinicians should be encouraged to deliver all aspects of evidence-based CBT, including behavioural change. The findings suggest that this will have a positive impact on both the early therapeutic alliance and later change in eating pathology. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Analysis of Charges Associated with Definitive Nonsurgical Therapy for Early-Stage Lateralized Tonsil Cancer.

    PubMed

    Lewis, Carol M; Chronowski, Gregory M; Dong, Wenli; Gunn, G Brandon; Rosenthal, David I; Weber, Randal S

    2015-08-01

    The cost of treatment as it affects comparative effectiveness is becoming increasingly more important. Because cost data are not readily available, we evaluated the charges associated with definitive nonsurgical therapy for early-stage lateralized tonsil cancers. Patients treated with unilateral radiation therapy (RT) for T1 or T2 tonsil cancer between 1995 and 2007 were retrospectively reviewed. Total and radiation-specific charges, from 3 months before to 4 months after radiation, were adjusted for inflation. All facets of treatment were evaluated for significant associations with total billing. Eighty-four patients were identified. Three-year overall survival, disease-specific survival, and recurrence-free survival were 97 % [95 % confidence interval (CI) 0.88-0.99], 98 % (95 % CI 0.89-1), and 96 % (95 % CI 0.88-0.99), respectively. The median for radiation-specific charges was $60,412 (range $16,811-$84,792). The median for total charges associated with treatment was $109,917 (range $36,680-$231,895). Total billing for treatment was significantly associated with the year of diagnosis (p = 0.008), intensity-modulated radiation therapy versus wedge pair RT (p = 0.005), preradiation direct laryngoscopy (p < 0.0001), chemotherapy (p < 0.0001), gastrostomy tube placement (p = 0.004), and postradiation neck dissection (p = 0.005). Although cost data for treatment are not readily available, historically, the recovery rate is approximately 30 %. The charges associated with definitive nonsurgical therapy for early-stage lateralized tonsil cancer have a wide range likely due to treatment-related procedures, the use of chemotherapy, and evolving RT technologies. These benchmark data are important given renewed interested in primary surgery for tonsil cancer. Cost of care, disease control, and functional outcomes will be critical for comparisons of effectiveness when selecting treatment modalities.

  15. Treatment decisions and the impact of adverse events before and during extended endocrine therapy in postmenopausal early breast cancer.

    PubMed

    Blok, Erik J; Kroep, Judith R; Meershoek-Klein Kranenbarg, Elma; Duijm-de Carpentier, Marjolijn; Putter, Hein; Liefers, Gerrit-Jan; Nortier, Johan W R; Rutgers, Emiel J Th; Seynaeve, Caroline M; van de Velde, Cornelis J H

    2018-05-01

    Extended endocrine therapy beyond 5 years for postmenopausal breast cancer has been studied within multiple phase III trials. Treatment compliance in these trials is generally poor. In this analysis, we aimed to determine factors that were associated with participation in the phase III Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial and with early treatment discontinuation, and how this influenced survival outcome. In the IDEAL trial, postmenopausal patients were randomised between 2.5 or 5 years of extended letrozole, after completing 5 years of endocrine therapy for hormone receptor-positive early breast cancer. A subgroup of this population participated earlier in the Tamoxifen Exemestane Adjuvant Multinational trial (5 years of exemestane or 2.5 years of tamoxifen followed by exemestane as primary adjuvant therapy) in which we explored which factors were determinative for enrolment in the IDEAL study. In the IDEAL cohort, we evaluated which factors predicted for early treatment discontinuation and the effect of early treatment discontinuation on disease-free survival (DFS). Nodal status, younger age and adjuvant chemotherapy were significantly associated with higher enrolment in the IDEAL trial. In the IDEAL cohort, adverse events (AEs), the type of primary endocrine therapy and the interval between primary and extended therapy were associated with early treatment discontinuation. Among the reported AEs, depressive feelings (56%) were most frequently associated with early treatment discontinuation. Early treatment discontinuation was not associated with worse DFS (hazard ratio [HR] = 1.02, 95% confidence interval = 0.76-1.37). In this analysis, we found that risk factors were most strongly associated enrolment in the IDEAL trial. In contrast, patient experiences were the most significant factors leading to early treatment discontinuation, with no effect on DFS. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Viruses and Antiviral Immunity in Drosophila

    PubMed Central

    Xu, Jie; Cherry, Sara

    2013-01-01

    Viral pathogens present many challenges to organisms, driving the evolution of a myriad of antiviral strategies to combat infections. A wide variety of viruses infect invertebrates, including both natural pathogens that are insect-restricted, and viruses that are transmitted to vertebrates. Studies using the powerful tools available in the model organism Drosophila have expanded our understanding of antiviral defenses against diverse viruses. In this review, we will cover three major areas. First, we will describe the tools used to study viruses in Drosophila. Second, we will survey the major viruses that have been studied in Drosophila. And lastly, we will discuss the well-characterized mechanisms that are active against these diverse pathogens, focusing on non-RNAi mediated antiviral mechanisms. Antiviral RNAi is discussed in another paper in this issue. PMID:23680639

  17. Antiviral Drug Research Proposal Activity †

    PubMed Central

    Injaian, Lisa; Smith, Ann C.; Shipley, Jennifer German; Marbach-Ad, Gili; Fredericksen, Brenda

    2011-01-01

    The development of antiviral drugs provides an excellent example of how basic and clinical research must be used together in order to achieve the final goal of treating disease. A Research Oriented Learning Activity was designed to help students to better understand how basic and clinical research can be combined toward a common goal. Through this project students gained a better understanding of the process of scientific research and increased their information literacy in the field of virology. The students worked as teams to research the many aspects involved in the antiviral drug design process, with each student becoming an “expert” in one aspect of the project. The Antiviral Drug Research Proposal (ADRP) culminated with students presenting their proposals to their peers and local virologists in a poster session. Assessment data showed increased student awareness and knowledge of the research process and the steps involved in the development of antiviral drugs as a result of this activity. PMID:23653735

  18. Viruses and antiviral immunity in Drosophila.

    PubMed

    Xu, Jie; Cherry, Sara

    2014-01-01

    Viral pathogens present many challenges to organisms, driving the evolution of a myriad of antiviral strategies to combat infections. A wide variety of viruses infect invertebrates, including both natural pathogens that are insect-restricted, and viruses that are transmitted to vertebrates. Studies using the powerful tools in the model organism Drosophila have expanded our understanding of antiviral defenses against diverse viruses. In this review, we will cover three major areas. First, we will describe the tools used to study viruses in Drosophila. Second, we will survey the major viruses that have been studied in Drosophila. And lastly, we will discuss the well-characterized mechanisms that are active against these diverse pathogens, focusing on non-RNAi mediated antiviral mechanisms. Antiviral RNAi is discussed in another paper in this issue. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Antiviral activity of silymarin against chikungunya virus

    PubMed Central

    Lani, Rafidah; Hassandarvish, Pouya; Chiam, Chun Wei; Moghaddam, Ehsan; Chu, Justin Jang Hann; Rausalu, Kai; Merits, Andres; Higgs, Stephen; Vanlandingham, Dana; Abu Bakar, Sazaly; Zandi, Keivan

    2015-01-01

    The mosquito-borne chikungunya virus (CHIKV) causes chikungunya fever, with clinical presentations such as severe back and small joint pain, and debilitating arthritis associated with crippling pains that persist for weeks and even years. Although there are several studies to evaluate the efficacy of drugs against CHIKV, the treatment for chikungunya fever is mainly symptom-based and no effective licensed vaccine or antiviral are available. Here, we investigated the antiviral activity of three types of flavonoids against CHIKV in vitro replication. Three compounds: silymarin, quercetin and kaempferol were evaluated for their in vitro antiviral activities against CHIKV using a CHIKV replicon cell line and clinical isolate of CHIKV of Central/East African genotype. A cytopathic effect inhibition assay was used to determine their activities on CHIKV viral replication and quantitative reverse transcription PCR was used to calculate virus yield. Antiviral activity of effective compound was further investigated by evaluation of CHIKV protein expression using western blotting for CHIKV nsP1, nsP3, and E2E1 proteins. Briefly, silymarin exhibited significant antiviral activity against CHIKV, reducing both CHIKV replication efficiency and down-regulating production of viral proteins involved in replication. This study may have important consequence for broaden the chance of getting the effective antiviral for CHIKV infection. PMID:26078201

  20. Prophylaxis Among Hepatitis B Core Antibody-positive Deceased-donor Liver Transplant Recipients: Hepatitis B Immunoglobulin Plus Oral Antiviral Agents Versus Antiviral Agents Alone: A Single-center Experience.

    PubMed

    Malik, Mohammad U; Ucbilek, Enver; Trilianos, Panagiotis; Cameron, Andrew M; Gurakar, Ahmet

    2017-04-01

    Hepatitis B core antibody immunoglobulin G seropositivity is evidence of past exposure to hepatitis B virus. Donor or recipient hepatitis B core antibody positivity may pose a risk of reactivation, especially early after liver transplant. Although most centers advocate using antiviral agents plus hepatitis B immunoglobulin, some have recently relied on antivirals only as prophylaxis after liver transplant. Here, we retrospectively investigated patient survival in hepatitis B core antibody-positive recipients, comparing those treated with antivirals plus hepatitis B immunoglobulin versus antivirals alone. After Internal Review Board approval, we reviewed medical records of deceased-donor liver transplant recipients between 1995 and 2013. Demographic characteristics, transplant indication, hepatitis B core antibody status, time to death, and type of posttransplant prophylaxis were recorded. We also recorded whether donors showed hepatitis B core antibody positivity. Patients who died within 30 days of liver transplant were excluded. There were 148 hepatitis B core antibody-positive recipients. Prophylaxis was given to 75 recipients after transplant: 8 (5%) received hepatitis B immunoglobulin, 22 (15%) received antivirals, and 45 (30%) received the combination. There were 34 deaths: 3 (38%) in hepatitis B immunoglobulin only, 3 (14%) in antiviral only, 8 (18%) in the combination, and 20 (27%) in no prophylaxis groups. One- and 5-year survival rates were similar for binary comparisons among prophylaxis groups (P > .05). Preliminary results support the current practice of using hepatitis B immunoglobulin plus antivirals for prophylaxis after liver transplant. The similar survival benefit with the combination versus antiviral agents alone suggests equal effectivity for prophylaxis posttransplant. However, a clear benefit of antivirals was not evident in our analysis. Future larger prospective studies are warranted to identify potential benefits of using antivirals alone

  1. Silas Weir Mitchell on epilepsy therapy in the late 19th to early 20th centuries.

    PubMed

    Burkholder, David B; Boes, Christopher J

    2014-11-01

    Silas Weir Mitchell (1829-1914), one of the fathers of American neurology, is well known for many contributions to neurology. However, his efforts in epilepsy are overshadowed by his other accomplishments. Mitchell introduced a new bromide preparation, lithium bromide, as a viable therapy. His most widely accepted contribution to the field was the introduction of inhaled amyl nitrite for early termination of seizures accompanied by an appropriate aura. Despite the prevalent views on lifestyle modification as a treatment for epilepsy during this time period, as well as Mitchell's own development of the "rest cure" for certain disease states, he was not a proponent of these types of interventions for epilepsy, nor did he support interventions focused on other organ systems, such as abdominal or gynecologic surgery. Mitchell had distinct opinions on the treatment of epilepsy, and helped to advance its therapeutics during his career.

  2. Early recombinant factor VIIa therapy in acute intracerebral hemorrhage: promising approach.

    PubMed

    Kumar, Sudhir; Badrinath, H R

    2006-03-01

    Intracerebral hemorrhage (ICH) is the most devastating form of stroke with a high morbidity and mortality. ICH constitutes about 20-30% of all strokes, with the prevalence being higher in Asian population. Treatment of ICH is predominantly conservative, which includes control of blood pressure, use of anti-cerebral edema measures such as mannitol and mechanical ventilation. The benefit of early surgery in ICH is debatable. Initial hematoma volume and subsequent growth in its size are important predictors of a poor outcome in ICH. This means that therapies aimed at preventing hematoma enlargement in the earliest possible window period could lead to a better outcome in ICH. Recombinant factor VIIa (rFVIIa) is one such agent, which has been shown to prevent hematoma expansion and improve outcome in acute ICH. The purpose of the current review is to focus on the evidence regarding the usefulness of rFVIIa in acute ICH.

  3. The role of progesterone therapy in early pregnancy: from physiological role to therapeutic utility.

    PubMed

    Czyzyk, Adam; Podfigurna, Agnieszka; Genazzani, Andrea Riccardo; Meczekalski, Blazej

    2017-06-01

    Progesterone is a steroid hormone of essential role in reproduction. In early pregnancy, it is responsible for preparation of endometrium for implantation process and maintenance of gestational sac in uterus, also by modulation of maternal immune system. Even though, several indices has been proposed as markers of endogenous progesterone synthesis (progesterone or luteinizing hormone measurements, endometrial biopsy), none has been proved to be reliable in detecting luteal phase defect. Currently, several pharmaceutical formulations are available, but in clinical setting the non-oral formulations seems to be effective in therapy. Progesterone is effective in the treatment of patients undergoing assisted reproductive technology procedure, as a luteal phase support. Some studies showed also its efficacy in the treatment of threatening or recurrent miscarriage, but newer trials neglected this beneficial effect. Due to controversies regarding utility of progesterone supplementation in these conditions, further studies are needed to address this issue.

  4. Early Toxicity in Patients Treated With Postoperative Proton Therapy for Locally Advanced Breast Cancer

    SciTech Connect

    Cuaron, John J.; Chon, Brian; Tsai, Henry

    Purpose: To report dosimetry and early toxicity data in breast cancer patients treated with postoperative proton radiation therapy. Methods and Materials: From March 2013 to April 2014, 30 patients with nonmetastatic breast cancer and no history of prior radiation were treated with proton therapy at a single proton center. Patient characteristics and dosimetry were obtained through chart review. Patients were seen weekly while on treatment, at 1 month after radiation therapy completion, and at 3- to 6-month intervals thereafter. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Frequencies of toxicities were tabulated. Results: Median dose delivered wasmore » 50.4 Gy (relative biological equivalent [RBE]) in 5 weeks. Target volumes included the breast/chest wall and regional lymph nodes including the internal mammary lymph nodes (in 93%). No patients required a treatment break. Among patients with >3 months of follow-up (n=28), grade 2 dermatitis occurred in 20 patients (71.4%), with 8 (28.6%) experiencing moist desquamation. Grade 2 esophagitis occurred in 8 patients (28.6%). Grade 3 reconstructive complications occurred in 1 patient. The median planning target volume V95 was 96.43% (range, 79.39%-99.60%). The median mean heart dose was 0.88 Gy (RBE) [range, 0.01-3.20 Gy (RBE)] for all patients, and 1.00 Gy (RBE) among patients with left-sided tumors. The median V20 of the ipsilateral lung was 16.50% (range, 6.1%-30.3%). The median contralateral lung V5 was 0.34% (range, 0%-5.30%). The median maximal point dose to the esophagus was 45.65 Gy (RBE) [range, 0-65.4 Gy (RBE)]. The median contralateral breast mean dose was 0.29 Gy (RBE) [range, 0.03-3.50 Gy (RBE)]. Conclusions: Postoperative proton therapy is well tolerated, with acceptable rates of skin toxicity. Proton therapy favorably spares normal tissue without compromising target coverage. Further follow-up is necessary to assess for clinical outcomes and

  5. Is Breast Conserving Therapy a Safe Modality for Early-Stage Male Breast Cancer?

    PubMed

    Zaenger, David; Rabatic, Bryan M; Dasher, Byron; Mourad, Waleed F

    2016-04-01

    Male breast cancer (MBC) is a rare disease and lacks data-based treatment guidelines. Most men are currently treated with modified radical mastectomy (MRM) or simple mastectomy (SM). We compared the oncologic treatment outcomes of early-stage MBC to determine whether breast conservation therapy (BCT) is appropriate. We searched the Surveillance, Epidemiology, and End Results database for MBC cases. That cohort was narrowed to cases of stage I-II, T1-T2N0 MBC with surgical and radiation therapy (RT) data available. The patients had undergone MRM, SM, or breast conservation surgery (BCS) with or without postoperative RT. We calculated the actuarial 5-year cause-specific survival (CSS). We identified 6263 MBC cases and included 1777 men with stage I or II, T1-T2, node-negative disease, who had the required treatment information available. MRM without RT was the most common treatment (43%). Only 17% underwent BCS. Of the BCS patients, 46% received adjuvant RT to complete the traditional BCT. No deaths were recorded in the BCT group, regardless of stage, or in the 3 stage I surgical groups if the men had received RT. The actuarial 5-year CSS was 100% in each BCT group. MRM alone resulted in an actuarial 5-year CSS of 97.3% for stage 1% and 91.2% for stage 2. The results from our study suggest that BCT for early-stage MBC yields comparable survival compared with more invasive treatment modalities (ie, MRM or SM alone). This could shift the treatment paradigm to less-invasive interventions and might have the added benefit of increased functional and psychological outcomes. Further prospective studies are needed to confirm our conclusions. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. A gene expression profile indicative of early stage HER2 targeted therapy response.

    PubMed

    O'Neill, Fiona; Madden, Stephen F; Clynes, Martin; Crown, John; Doolan, Padraig; Aherne, Sinéad T; O'Connor, Robert

    2013-07-01

    Efficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies. Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change. In these HER2-expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor.Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.

  7. A gene expression profile indicative of early stage HER2 targeted therapy response

    PubMed Central

    2013-01-01

    Background Efficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies. Results Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change. Conclusions In these HER2-expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor. Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents. PMID:23816254

  8. Cognitive Enhancement Therapy Improves Resting-State Functional Connectivity in Early Course Schizophrenia

    PubMed Central

    Eack, Shaun M.; Newhill, Christina E.; Keshavan, Matcheri S.

    2016-01-01

    Objective Cognitive remediation is emerging as an effective psychosocial intervention for addressing untreated cognitive and functional impairments in persons with schizophrenia, and might achieve its benefits through neuroplastic changes in brain connectivity. This study seeks to examine the effects of cognitive enhancement therapy (CET) on fronto-temporal brain connectivity in a randomized controlled trial with individuals in the early course of schizophrenia. Method Stabilized, early course outpatients with schizophrenia or schizoaffective disorder (N = 41) were randomly assigned to CET (n = 25) or an active enriched supportive therapy (EST) control (n = 16) and treated for 2 years. Functional MRI data were collected annually, and pseudo resting-state functional connectivity analysis was used to examine differential changes in fronto-temporal connectivity between those treated with CET compared with EST. Results Individuals receiving CET evidenced significantly less functional connectivity loss between the resting-state network and the left dorsolateral prefrontal cortex as well as significantly increased connectivity with the right insular cortex compared to EST (all corrected p < .01). These neural networks are involved in emotion processing and problem-solving. Increased connectivity with the right insula significantly mediated CET effects on improved emotion perception (z′ = −1.96, p = .021), and increased connectivity with the left dorsolateral prefrontal cortex mediated CET-related improvements in emotion regulation (z′ = −1.71, p = .052). Conclusions These findings provide preliminary evidence that CET, a psychosocial cognitive remediation intervention, may enhance connectivity between frontal and temporal brain regions implicated in problem-solving and emotion processing in service of cognitive enhancement in schizophrenia. PMID:27713804

  9. Impact of pretransplant rifaximin therapy on early post-liver transplant infections.

    PubMed

    Esfeh, Jamak Modaresi; Hanouneh, Ibrahim A; Koval, Christine E; Kovacs, Christopher; Dalal, Deepan S; Ansari-Gilani, Kianoush; Confer, Bradley D; Eghtesad, Bijan; Zein, Nizar N; Menon, K V Narayanan

    2014-05-01

    Bacterial and fungal infections are major causes of morbidity and mortality after liver transplantation (LT). The role of intestinal decontamination in the prevention of post-LT infections is controversial. Rifaximin is widely used for the treatment of hepatic encephalopathy. The effect of rifaximin on post-LT infections is unknown. The aim of our study was to determine the effect of rifaximin therapy in the pretransplant period on early bacterial infections (EBIs) and fungal infections within the first 30 days after LT. All adult patients who underwent LT at our institution (January 2009 to July 2011) were included in this retrospective cohort study. Patients receiving antibiotics other than pretransplant protocol antibiotics were excluded. Patients were stratified into 2 groups based on the presence or absence of rifaximin therapy for at least 2 days before LT. Infections were defined by the isolation of any bacterial or fungal organisms within 30 days of LT. Multivariate regression analysis, Student t tests, and Pearson's chi-square tests were used to compare the 2 groups. Two hundred sixty-eight patients were included, and 71 of these patients (26.5%) were on rifaximin at the time of LT. The 2 groups were comparable with respect to age, sex, race, and Model for End-Stage Liver Disease score. There were no significant differences in the rates of EBIs (30% for the non-rifaximin group and 25% for the rifaximin group, P = 0.48) or fungal infections between the 2 groups. There was no increase in antimicrobial resistance among the infecting organisms. There was no difference in survival between the rifaximin and non-rifaximin groups (98% versus 97%, P = 0.36). In conclusion, the use of rifaximin in the pre-LT period was not associated with an increased risk of bacterial or fungal infections in the early post-LT period. © 2014 American Association for the Study of Liver Diseases.

  10. The Effect of Combination Antiviral Therapy in the Treatment of Hepatitis C on the Occurrence of Depressive Disorder in Patients Treated for Hepatitis C in the Republic of Srpska.

    PubMed

    Banjac, Visnja; Zivlak-Radulovic, Nera; Miskovic, Mirjana

    2016-04-01

    The current standard treatment of chronic hepatitis C in Bosnia and Herzegovina consists of pegylated interferon alpha in combination with ribavirin. Interferon therapy has many psychiatric side effects, with depressive symptomatology being most prominent. The aim of the study was to establish the frequency and severity of depression in patients with chronic hepatitis C during two months of the aforementioned therapy. The overall sample consisted of 46 subjects, divided into three subgroups, aged 18 to 65. The study population consisted of subjects treated for chronic hepatitis C (n = 15), subjects infected but not treated for chronic hepatitis C (n = 15), and healthy controls (n = 16). The assessment and level of depression were based on the Structural clinical interview (SCID), Montgomery-Asberg Depression Rating Scale and Zung Self-Rating Depression Scale. The assessments were conducted before interferon therapy (on the day 0), after 4 and 8 weeks of therapy. Regarding its frequency, MADRS scoring showed that the number of depressed subjects receiving therapy increased after 8 weeks (46.7%). There was statistical significance between the subgroups after 4 and 8 weeks. Likewise, the ZUNG scale showed that the number of depressed subjects receiving therapy increased after 8 weeks (73.3%). There was statistical significance between the subgroups on the day 0, after 4 and 8 weeks. Depression was significantly more frequent in chronic hepatitis C subjects treated with interferon alpha in combination with ribavirin than in subjects in the group without therapy. Mild depression was most prevalent.

  11. Longitudinal functional brain imaging study in early course schizophrenia before and after cognitive enhancement therapy.

    PubMed

    Keshavan, Matcheri S; Eack, Shaun M; Prasad, Konasale M; Haller, Chiara S; Cho, Raymond Y

    2017-05-01

    Schizophrenia is characterized by impaired -social and non social cognition both of which lead to functional deficits. These deficits may benefit from cognitive remediation, but the neural underpinnings of such improvements have not been clearly delineated. We conducted a functional magnetic resonance (fMRI) study in early course schizophrenia patients randomly assigned to cognitive enhancement therapy (CET) or enriched supportive therapy (EST) and treated for two years. Imaging data over three time points including fMRI blood oxygen level dependent (BOLD) data were acquired during performance of a cognitive control paradigm, the Preparing to Overcome Prepotency (POP) task, and functional connectivity data, were analyzed. During the two years of treatment, CET patients showed a continual increase in BOLD activity in the right dorsolateral prefrontal cortex (DLPFC), whereas EST patients tended to show no change in prefrontal brain function throughout treatment. Increases in right DLPFC activity were modestly associated with improved neurocognition (β = .14, p = .041), but not social cognition. Functional connectivity analyses showed reduced connectivity between the DLPFC and the anterior cingulate cortex (ACC) in CET compared to EST over the two years of treatment, which was associated with neurocognitive improvement. These findings suggest that CET leads to enhanced neural activity in brain regions mediating cognitive control and increased efficiency in prefrontal circuits; such changes may be related to the observed therapeutic effects of CET on neurocognitive function. Copyright © 2017. Published by Elsevier Inc.

  12. Predicting nonadherence to adjuvant endocrine therapy in women with early stage breast cancer.

    PubMed

    Corter, Arden L; Broom, Reuben; Porter, David; Harvey, Vernon; Findlay, Michael

    2018-05-18

    Failing to take endocrine therapy (ET) as prescribed (nonadherence) increases risk of morbidity and mortality from breast cancer recurrence. We explored predictors of nonadherence, including demographic, clinical, treatment, and personal factors, among women newly prescribed ET for early stage breast cancer. We also examined predictors of their thoughts about stopping treatment (TST). A baseline survey prior to ET assessed demographics, illness beliefs, beliefs about medicines, fear of recurrence, symptoms, and negative affect. A follow-up survey at 3 months repeated these measures with additional questions about nonadherence and TST. Nonadherence and TST were analyzed using logistic and multiple regression, respectively. Patient record review provided clinical data. The baseline survey was completed by 125 women, with a 96% retention rate at follow-up. Thirty-six percent reported nonadherence, and 30% reported TST. Results of regression analyses showed that TST was most strongly associated with symptom severity at follow-up, whereas, lower coherence beliefs, and the absence of comorbid conditions were the strongest predictors of actual nonadherence. This is the first longitudinal study to examine concurrently the association of demographic, personal and treatment factors with nonadherence, and TST. Findings have potentially important clinical implications; interventions to improve adherence and reduce TST may need to target women's understanding of their diagnosis and treatment, illness beliefs, and symptoms prior to starting therapy. Copyright © 2018 John Wiley & Sons, Ltd.

  13. Monitoring early tumor response to drug therapy with diffuse optical tomography

    NASA Astrophysics Data System (ADS)

    Flexman, Molly L.; Vlachos, Fotios; Kim, Hyun Keol; Sirsi, Shashank R.; Huang, Jianzhong; Hernandez, Sonia L.; Johung, Tessa B.; Gander, Jeffrey W.; Reichstein, Ari R.; Lampl, Brooke S.; Wang, Antai; Borden, Mark A.; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

    2012-01-01

    Although anti-angiogenic agents have shown promise as cancer therapeutics, their efficacy varies between tumor types and individual patients. Providing patient-specific metrics through rapid noninvasive imaging can help tailor drug treatment by optimizing dosages, timing of drug cycles, and duration of therapy--thereby reducing toxicity and cost and improving patient outcome. Diffuse optical tomography (DOT) is a noninvasive three-dimensional imaging modality that has been shown to capture physiologic changes in tumors through visualization of oxygenated, deoxygenated, and total hemoglobin concentrations, using non-ionizing radiation with near-infrared light. We employed a small animal model to ascertain if tumor response to bevacizumab (BV), an anti-angiogenic agent that targets vascular endothelial growth factor (VEGF), could be detected at early time points using DOT. We detected a significant decrease in total hemoglobin levels as soon as one day after BV treatment in responder xenograft tumors (SK-NEP-1), but not in SK-NEP-1 control tumors or in non-responder control or BV-treated NGP tumors. These results are confirmed by magnetic resonance imaging T2 relaxometry and lectin perfusion studies. Noninvasive DOT imaging may allow for earlier and more effective control of anti-angiogenic therapy.

  14. Early MRI changes in glioblastoma in the period between surgery and adjuvant therapy.

    PubMed

    Farace, Paolo; Amelio, Dante; Ricciardi, Giuseppe K; Zoccatelli, Giada; Magon, Stefano; Pizzini, Francesca; Alessandrini, Franco; Sbarbati, Andrea; Amichetti, Maurizio; Beltramello, Alberto

    2013-01-01

    To investigate the increase in MRI contrast enhancement (CE) occurring in glioblastoma during the period between surgery and initiation of chemo-radiotherapy, thirty-seven patients with newly diagnosed glioblastoma were analyzed by early post-operative magnetic resonance (EPMR) imaging within three days of surgery and by pre-adjuvant magnetic resonance (PAMR) examination before adjuvant therapy. Areas of new CE were investigated by use of EPMR diffusion-weighted imaging and PAMR perfusion imaging (by arterial spin-labeling). PAMR was acquired, on average, 29.9 days later than EPMR (range 20-37 days). During this period an increased area of CE was observed for 17/37 patients. For 3/17 patients these regions were confined to areas of reduced EPMR diffusion, suggesting postsurgical infarct. For the other 14/17 patients, these areas suggested progression. For 11/17 patients the co-occurrence of hyperperfusion in PAMR perfusion suggested progression. PAMR perfusion and EPMR diffusion did not give consistent results for 3/17 patients for whom small new areas of CE were observed, presumably because of the poor spatial resolution of perfusion imaging. Before initiation of adjuvant therapy, areas of new CE of resected glioblastomas are frequently observed. Most of these suggest tumor progression, according to EPMR diffusion and PAMR perfusion criteria.

  15. Domestic dengue infection with hemophagocytic lymphohistiocytosis successfully treated by early steroid therapy.

    PubMed

    Yoshifuji, Kota; Oshina, Takahiro; Sonokawa, Saeko; Noguchi, Yuma; Suzuki, Sayaka; Tanaka, Keisuke; Kumagai, Takashi

    2016-07-01

    A 34-year-old man, working at a park in Tokyo, Japan, was repeatedly bitten by mosquitoes while cutting grass. He was hospitalized with sudden fever, fatigue, and weakness. He was eventually diagnosed with dengue virus infection, detected using reverse transcription polymerase chain reaction for the genome and by the presence of nonstructural protein 1 in his peripheral blood. Symptomatic treatments such as acetaminophen for the fever were not effective. Moreover, peripheral blood examination showed drastically decreased white blood cells and platelets, as well as marked elevations of ferritin and soluble interleukin 2 receptor. Furthermore, bone marrow examination revealed increased macrophages with hemophagocytosis. Dengue infection with hemophagocytic lymphohistiocytosis (HLH) was ultimately diagnosed. Half-dose steroid pulse therapy for three days dramatically reduced his temperature, thereby ameliorating physical symptoms and restoring normal peripheral blood data. He was discharged 12 days after admission. Dengue infection with HLH is rare and this is the first report, to our knowledge, of domestic dengue infection with HLH in Japan. Early steroid therapy may be effective in such cases.

  16. Adjuvant therapy in early-stage non-small cell lung cancer.

    PubMed

    Serke, Monika

    2010-01-01

    Evidence clearly supports adjuvant chemotherapy following resection in patients with stage II or III non-small cell lung cancer (NSCLC). Based on 3 landmark studies, adjuvant chemotherapy has become standard in completely resected NSCLC stage II and IIIA. Survival benefit from adjuvant chemotherapy is estimated to be between 3% and 15%, depending on stage. Treatment should include 4 cycles of platinum-based combination chemotherapy. There is uncertainty about chemotherapy prescription in those patients with resected stage IB NSCLC, as the risk of recurrence is lower in early NSCLC and the magnitude of benefit of adjuvant therapy is proportional to the risk of relapse according to stage. Postoperative radiotherapy (PORT) should not be used for stage I or II NSCLC, and remains controversial in resected stage IIIA (N2) disease. All positive adjuvant trials have utilized a cisplatin-based regimen, usually in combination with vinorelbine, and this should be considered the standard approach. Prognostic factors to select patients who will benefit from adjuvant therapy in general or from platinum-based chemotherapy are under discussion, but not yet established. In future we hope to optimize treatment convenience for the patients by using other combinations with the hope of better efficacy results. Work is currently under way to identify prognostic factors which in future may help to identify patients who are most likely to benefit from chemotherapy. Copyright 2010 S. Karger AG, Basel.

  17. Early changes of procalcitonin may advise about prognosis and appropriateness of antimicrobial therapy in sepsis.

    PubMed

    Georgopoulou, Antonia-Panagiota; Savva, Athina; Giamarellos-Bourboulis, Evangelos J; Georgitsi, Marianna; Raftogiannis, Maria; Antonakos, Nicolaos; Apostolidou, Efterpi; Carrer, Dionyssia-Pinelopi; Dimopoulos, George; Economou, Aggelos; Efthymiou, George; Galanakis, Nearchos; Galani, Labrini; Gargalianos, Panagiotis; Karaiskos, Ilias; Katsenos, Chrisostomos; Kavatha, Dimitra; Koratzanis, Evangelos; Labropoulos, Panagiotis; Lada, Malvina; Nakos, George; Paggalou, Evgenia; Panoutsopoulos, George; Paraschos, Michael; Pavleas, Ioannis; Pontikis, Konstantinos; Poulakou, Garyfallia; Prekates, Athanassios; Sybardi, Styliani; Theodorakopoulou, Maria; Trakatelli, Christina; Tsiaoussis, Panagiotis; Gogos, Charalambos; Giamarellou, Helen; Armaganidis, Apostolos; Meisner, Michael

    2011-06-01

    The objective of this study is to define if early changes of procalcitonin (PCT) may inform about prognosis and appropriateness of administered therapy in sepsis. A prospective multicenter observational study was conducted in 289 patients. Blood samples were drawn on day 1, that is, within less than 24 hours from advent of signs of sepsis, and on days 3, 7, and 10. Procalcitonin was estimated in serum by the ultrasensitive Kryptor assay (BRAHMS GmbH, Hennigsdorf, Germany). Patients were divided into the following 2 groups according to the type of change of PCT: group 1, where PCT on day 3 was decreased by more than 30% or was below 0.25 ng/mL, and group 2, where PCT on day 3 was either increased above 0.25 ng/mL or decreased less than 30%. Death occurred in 12.3% of patients of group 1 and in 29.9% of those of group 2 (P < .0001). Odds ratio for death of patients of group 1 was 0.328. Odds ratio for the administration of inappropriate antimicrobials of patients of group 2 was 2.519 (P = .003). Changes of serum PCT within the first 48 hours reflect the benefit or not of the administered antimicrobial therapy. Serial PCT measurements should be used in clinical practice to guide administration of appropriate antimicrobials. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Developing laser-based therapy monitoring of early caries in pediatric dental settings

    NASA Astrophysics Data System (ADS)

    Zhou, Yaxuan; Jiang, Yang; Kim, Amy S.; Xu, Zheng; Berg, Joel H.; Seibel, Eric J.

    2017-02-01

    Optical imaging modalities and therapy monitoring protocols are required for the emergence of non-surgical interventions for treating infections in teeth to remineralize the enamel. Current standard of visual inspection, tactile probing and radiograph for caries detection is not highly sensitive, quantitative, and safe. Furthermore, the latter two are not viable options for interproximal caries. We present preliminary results of multimodal laser-based imaging and uorescence spectroscopy in a blinded clinical study comparing two topical therapies of early interproximal caries in children. With a spacer placed interproximally both at baseline and followup examinations, the 405-nm excited red porphyrin uorescence imaging with green auto uorescence is measured and compared to a 12-month follow-up. 405-nm laser-induced uorescence spectroscopy is also measured from the center of selected multimodal video imaging frames. These results of three subjects are analyzed both qualitatively by comparing spectra and quantitatively based on uorescence region segmentation, and then are compared to the standard of care(visual examination and radiograph interpretation). Furthermore, this study points out challenges associated with optically monitoring non-surgical dental interventions over long periods of time in clinical practice and also indicates future direction for improvement on the protocol.

  19. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update.

    PubMed

    Denduluri, Neelima; Chavez-MacGregor, Mariana; Telli, Melinda L; Eisen, Andrea; Graff, Stephanie L; Hassett, Michael J; Holloway, Jamie N; Hurria, Arti; King, Tari A; Lyman, Gary H; Partridge, Ann H; Somerfield, Mark R; Trudeau, Maureen E; Wolff, Antonio C; Giordano, Sharon H

    2018-05-22

    Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

  20. Cognitive behavioural therapy attenuates the enhanced early facial stimuli processing in social anxiety disorders: an ERP investigation.

    PubMed

    Cao, Jianqin; Liu, Quanying; Li, Yang; Yang, Jun; Gu, Ruolei; Liang, Jin; Qi, Yanyan; Wu, Haiyan; Liu, Xun

    2017-07-28

    Previous studies of patients with social anxiety have demonstrated abnormal early processing of facial stimuli in social contexts. In other words, patients with social anxiety disorder (SAD) tend to exhibit enhanced early facial processing when compared to healthy controls. Few studies have examined the temporal electrophysiological event-related potential (ERP)-indexed profiles when an individual with SAD compares faces to objects in SAD. Systematic comparisons of ERPs to facial/object stimuli before and after therapy are also lacking. We used a passive visual detection paradigm with upright and inverted faces/objects, which are known to elicit early P1 and N170 components, to study abnormal early face processing and subsequent improvements in this measure in patients with SAD. Seventeen patients with SAD and 17 matched control participants performed a passive visual detection paradigm task while undergoing EEG. The healthy controls were compared to patients with SAD pre-therapy to test the hypothesis that patients with SAD have early hypervigilance to facial cues. We compared patients with SAD before and after therapy to test the hypothesis that the early hypervigilance to facial cues in patients with SAD can be alleviated. Compared to healthy control (HC) participants, patients with SAD had more robust P1-N170 slope but no amplitude effects in response to both upright and inverted faces and objects. Interestingly, we found that patients with SAD had reduced P1 responses to all objects and faces after therapy, but had selectively reduced N170 responses to faces, and especially inverted faces. Interestingly, the slope from P1 to N170 in patients with SAD was flatter post-therapy than pre-therapy. Furthermore, the amplitude of N170 evoked by the facial stimuli was correlated with scores on the interaction anxiousness scale (IAS) after therapy. Our results did not provide electrophysiological support for the early hypervigilance hypothesis in SAD to faces, but

  1. The effects of very early mirror therapy on functional improvement of the upper extremity in acute stroke patients.

    PubMed

    Yeldan, Ipek; Huseyınsınoglu, Burcu Ersoz; Akıncı, Buket; Tarakcı, Ela; Baybas, Sevim; Ozdıncler, Arzu Razak

    2015-11-01

    [Purpose] The aim of the study was to evaluate the effects of a very early mirror therapy program on functional improvement of the upper extremity in acute stroke patients. [Subjects] Eight stroke patients who were treated in an acute neurology unit were included in the study. [Methods] The patients were assigned alternatively to either the mirror therapy group receiving mirror therapy and neurodevelopmental treatment or the neurodevelopmental treatment only group. The primary outcome measures were the upper extremity motor subscale of the Fugl-Meyer Assessment, Motricity Index upper extremity score, and the Stroke Upper Limb Capacity Scale. Somatosensory assessment with the Ayres Southern California Sensory Integration Test, and the Barthel Index were used as secondary outcome measures. [Results] No statistically significant improvements were found for any measures in either group after the treatment. In terms of minimally clinically important differences, there were improvements in Fugl-Meyer Assessment and Barthel Index in both mirror therapy and neurodevelopmental treatment groups. [Conclusion] The results of this pilot study revealed that very early mirror therapy has no additional effect on functional improvement of upper extremity function in acute stroke patients. Multicenter trials are needed to determine the results of early application of mirror therapy in stroke rehabilitation.

  2. Cost-effectiveness of early compared to late inhaled nitric oxide therapy in near-term infants.

    PubMed

    Armstrong, Edward P; Dhanda, Rahul

    2010-12-01

    The purpose of this study was to determine the cost-effectiveness of early versus late inhaled nitric oxide (INO) therapy in neonates with hypoxic respiratory failure initially managed on conventional mechanical ventilation. A decision analytic model was created to compare the use of early INO compared to delayed INO for neonates receiving mechanical ventilation due to hypoxic respiratory failure. The perspective of the model was that of a hospital. Patients who did not respond to either early or delayed INO were assumed to have been treated with extracorporeal membrane oxygenation (ECMO). The effectiveness measure was defined as a neonate discharged alive without requiring ECMO therapy. A Monte Carlo simulation of 10,000 cases was conducted using first and second order probabilistic analysis. Direct medical costs that differed between early versus delayed INO treatment were estimated until time to hospital discharge. The proportion of successfully treated patients and costs were determined from the probabilistic sensitivity analysis. The mean (± SD) effectiveness rate for early INO was 0.75 (± 0.08) and 0.61 (± 0.09) for delayed INO. The mean hospital cost for early INO was $21,462 (± $2695) and $27,226 (± $3532) for delayed INO. In 87% of scenarios, early INO dominated delayed INO by being both more effective and less costly. The acceptability curve between products demonstrated that early INO had over a 90% probability of being the most cost-effective treatment across a wide range of willingness to pay values. This analysis indicated that early INO therapy was cost-effective in neonates with hypoxic respiratory failure requiring mechanical ventilation compared to delayed INO by reducing the probability of developing severe hypoxic respiratory failure. There was a 90% or higher probability that early INO was more cost-effective than delayed INO across a wide range of willingness to pay values in this analysis.

  3. Antenatal Workup of Early Megacystis and Selection of Candidates for Fetal Therapy.

    PubMed

    Fontanella, Federica; Duin, Leonie; Adama van Scheltema, Phebe N; Cohen-Overbeek, Titia E; Pajkrt, Eva; Bekker, Mireille; Willekes, Christine; Bax, Caroline J; Oepkes, Dick; Bilardo, Catia M

    2018-05-17

    To investigate the best criteria for discriminating fetuses with isolated posterior urethral valves from those theoretically not eligible for fetal treatment because of complex megacystis, high chance of spontaneous resolution, and urethral atresia. A retrospective national study was conducted in fetuses with megacystis detected before 17 weeks' gestation (early megacystis). In total, 142 cases with fetal megacystis were included in the study: 52 with lower urinary tract obstruction, 29 with normal micturition at birth, and 61 with miscellaneous syndromal associations, chromosomal and multiple structural abnormalities (complex megacystis). Only a nuchal translucency > 95th centile, and not a longitudinal bladder diameter ≤15 mm (p = 0.24), significantly increased the risk of complex megacystis (p < 0.01). Cases with a high chance of spontaneous resolution were identified by using the cut-off of 12 mm, as demonstrated in a previous study, and the finding of an associated umbilical cord cyst carried a high-risk of urethral atresia (odds ratio: 15; p = 0.026), an unfavorable condition for antenatal treatment. An algorithm encompassing these three criteria demonstrated good accuracy in selecting fetuses theoretically eligible for fetal treatment (specificity 73%; sensitivity 92%). Cases theoretically eligible for early fetal therapy are those with normal nuchal translucency, a longitudinal bladder diameter > 12 mm, and without ultrasound evidence of umbilical cord cysts. © 2018 The Author(s) Published by S. Karger AG, Basel.

  4. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause.

    PubMed

    Sullivan, Shannon D; Sarrel, Philip M; Nelson, Lawrence M

    2016-12-01

    Primary ovarian insufficiency (POI) is a rare but important cause of ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal ovarian hormone production and continuing HRT until the normal age of natural menopause, ∼50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or ovarian cancer, women approaching the age of natural menopause, and breastfeeding women. Published by Elsevier Inc.

  5. Early pulmonary toxicity following lung stereotactic body radiation therapy delivered in consecutive daily fractions.

    PubMed

    Stauder, Michael C; Macdonald, O Kenneth; Olivier, Kenneth R; Call, Jason A; Lafata, Kyle; Mayo, Charles S; Miller, Robert C; Brown, Paul D; Bauer, Heather J; Garces, Yolanda I

    2011-05-01

    Identify the incidence of early pulmonary toxicity in a cohort of patients treated with lung stereotactic body radiation therapy (SBRT) on consecutive treatment days. A total of 88 lesions in 84 patients were treated with SBRT in consecutive daily fractions (Fx) for medically inoperable non-small cell lung cancer or metastasis. The incidence of pneumonitis was evaluated and graded according to the NCI CTCAE v3.0. With a median follow-up of 15.8 months (range 2.5-28.6), the median age at SBRT was 71.8 years (range 23.8-87.8). 47 lesions were centrally located and 41 were peripheral. Most central lesions were treated with 48Gy in 4 Fx, and most peripheral lesions with 54Gy in 3 Fx. The incidence of grade ≥ 2 pneumonitis was 12.5% in all patients treated, and 14.3% among the subset of patients treated with 54Gy in 3 Fx. A total of two grade 3 toxicities were seen as one grade 5 toxicity in a patient treated for recurrence after pneumonectomy. Treating both central and peripheral lung lesions with SBRT in consecutive daily fractions in this cohort was well tolerated and did not cause excessive early pulmonary toxicity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  6. Chemotherapy causes cancer! A case report of therapy related acute myeloid leukaemia in early stage breast cancer.

    PubMed

    Aidan, J Cole; Priddee, Nicole R; McAleer, James J

    2013-05-01

    Use of chemotherapy and radiotherapy in the adjuvant setting has improved survival for many patients with malignancy. Unfortunately multimodality treatment can come at a price, in particular therapy-related malignancies. This has importance in that patients must be made aware of this potential detriment from therapy and doctors must consider this diagnosis in those patients who are cancer survivors and presenting with health problems. We present a case report and brief overview of the literature regarding chemotherapy-induced acute myeloid leukaemia (AML) following therapy for early stage breast cancer.

  7. Dosimetric evaluation of radionuclides for VCAM-1-targeted radionuclide therapy of early brain metastases.

    PubMed

    Falzone, Nadia; Ackerman, Nicole L; Rosales, Liset de la Fuente; Bernal, Mario A; Liu, Xiaoxuan; Peeters, Sarah Gja; Soto, Manuel Sarmiento; Corroyer-Dulmont, Aurélien; Bernaudin, Myriam; Grimoin, Elisa; Touzani, Omar; Sibson, Nicola R; Vallis, Katherine A

    2018-01-01

    Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of α-emitting radionuclides, 149 Tb, 211 At, 212 Pb, 213 Bi and 225 Ac; β-emitting radionuclides, 90 Y, 161 Tb and 177 Lu; and Auger electron (AE)-emitters 67 Ga, 89 Zr, 111 In and 124 I, for targeted radionuclide therapy (TRT). Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative β- and α-emitters, 177 Lu and 212 Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. 177 Lu produced 2.69 ± 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 µm. The DSB yield of 212 Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV α-emissions from decay products, 212 Bi and 212 Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield 212 Pb may be more effective for short range targeting of early micrometastatic lesions than 177 Lu. MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of α-, β- and AE-emitting radionuclides for TRT. 212 Pb, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE.

  8. Early Postmenopausal Transdermal 17β-Estradiol Therapy and Amyloid-β Deposition.

    PubMed

    Kantarci, Kejal; Lowe, Val J; Lesnick, Timothy G; Tosakulwong, Nirubol; Bailey, Kent R; Fields, Julie A; Shuster, Lynne T; Zuk, Samantha M; Senjem, Matthew L; Mielke, Michelle M; Gleason, Carey; Jack, Clifford R; Rocca, Walter A; Miller, Virginia M

    2016-05-07

    It remains controversial whether hormone therapy in recently postmenopausal women modifies the risk of Alzheimer's disease (AD). To investigate the effects of hormone therapy on amyloid-β deposition in recently postmenopausal women. Participants within 5-36 months past menopause in the Kronos Early Estrogen Prevention Study, a randomized, double blinded placebo-controlled clinical trial, were randomized to: 1) 0.45 mg/day oral conjugated equine estrogens (CEE); 2) 50μg/day transdermal 17β-estradiol; or 3) placebo pills and patch for four years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. 11C Pittsburgh compound B (PiB) PET imaging was performed in 68 of the 118 participants at Mayo Clinic approximately seven years post randomization and three years after stopping randomized treatment. PiB Standard unit value ratio (SUVR) was calculated. Women (age = 52-65) randomized to transdermal 17β-estradiol (n = 21) had lower PiB SUVR compared to placebo (n = 30) after adjusting for age [odds ratio (95% CI) = 0.31(0.11-0.83)]. In the APOEɛ4 carriers, transdermal 17β-estradiol treated women (n = 10) had lower PiB SUVR compared to either placebo (n = 5) [odds ratio (95% CI) = 0.04(0.004-0.44)], or the oral CEE treated group (n = 3) [odds ratio (95% CI) = 0.01(0.0006-0.23)] after adjusting for age. Hormone therapy was not associated with PiB SUVR in the APOEɛ4 non-carriers. In this pilot study, transdermal 17β-estradiol therapy in recently postmenopausal women was associated with a reduced amyloid-β deposition, particularly in APOEɛ4 carriers. This finding may have important implications for the prevention of AD in postmenopausal women, and needs to be confirmed in a larger sample.

  9. Early ICU Standardized Rehabilitation Therapy for the Critically Injured Burn Patient

    DTIC Science & Technology

    2016-10-01

    physical therapy , respiratory therapy and related disciplines. Accordingly, the investigators feel that the proposed continuation plan will both fall... physical therapy , and progressive resistance exercise. The usual care group received weekday physical therapy when ordered by the clinical team. For the... physical therapy , and 3.0 (1.0-5.0) for progressive resistance exercise. Themedian days of delivery of physical therapy for the usual care group was 1.0

  10. Increasing Early Childhood Educators' Use of Communication-Facilitating and Language-Modelling Strategies: Brief Speech and Language Therapy Training

    ERIC Educational Resources Information Center

    McDonald, David; Proctor, Penny; Gill, Wendy; Heaven, Sue; Marr, Jane; Young, Jane

    2015-01-01

    Intensive Speech and Language Therapy (SLT) training courses for Early Childhood Educators (ECEs) can have a positive effect on their use of interaction strategies that support children's communication skills. The impact of brief SLT training courses is not yet clearly understood. The aims of these two studies were to assess the impact of a brief…

  11. Simultaneous titration and phenotypic antiviral drug susceptibility testing for herpes simplex virus 1 and 2.

    PubMed

    Tardif, Keith D; Jorgensen, Shane; Langer, Janine; Prichard, Mark; Schlaberg, Robert

    2014-11-01

    Most herpes simplex virus (HSV) isolates from treatment-naïve patients are susceptible to antivirals. However, prolonged antiviral therapy can select for drug-resistant strains, especially in immunocompromised patients. Standard phenotypic methods for antiviral resistance testing are labor and time-intense and molecular resistance determinants are insufficiently understood for routine diagnostic use of genotypic resistance testing. To enable rapid, scalable antiviral susceptibility testing and minimize viral passage, we developed a 7-day, 96-well assay for simultaneous HSV 1/2 titration and phenotypic resistance testing for acyclovir and foscarnet. The assay was optimized and validated by testing clinical isolates and laboratory strains (n=39) with known IC50 for acyclovir (23 resistant) and foscarnet (1 resistant) based on plaque reduction or dye-uptake assays. A chemiluminescent detection reagent is used for quantification of cytopathic effect instead of plaque counting or measuring dye-uptake. Drug concentrations inhibiting 50% of chemiluminescent signal reduction (IC50) were determined concurrently at each of three virus dilutions. Results agree for 92.3% (acyclovir) and 100% (foscarnet) of isolates. For all three discordant samples, results of reference testing by plaque reduction agreed with the chemiluminescent assay. Reproducibility studies showed 100% qualitative agreement and 3-37% coefficient of variation based on IC50. Chemiluminescence detection as a surrogate for cellular viability with an automated plate reader provides improved throughput and workflow, as well as high accuracy and reproducibility for antiviral drug susceptibility testing. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Cytotoxic, Virucidal, and Antiviral Activity of South American Plant and Algae Extracts

    PubMed Central

    Faral-Tello, Paula; Mirazo, Santiago; Dutra, Carmelo; Pérez, Andrés; Geis-Asteggiante, Lucía; Frabasile, Sandra; Koncke, Elina; Davyt, Danilo; Cavallaro, Lucía; Heinzen, Horacio; Arbiza, Juan

    2012-01-01

    Herpes simplex virus type 1 (HSV-1) infection has a prevalence of 70% in the human population. Treatment is based on acyclovir, valacyclovir, and foscarnet, three drugs that share the same mechanism of action and of which resistant strains have been isolated from patients. In this aspect, innovative drug therapies are required. Natural products offer unlimited opportunities for the discovery of antiviral compounds. In this study, 28 extracts corresponding to 24 plant species and 4 alga species were assayed in vitro to detect antiviral activity against HSV-1. Six of the methanolic extracts inactivated viral particles by direct interaction and 14 presented antiviral activity when incubated with cells already infected. Most interesting antiviral activity values obtained are those of Limonium brasiliense, Psidium guajava, and Phyllanthus niruri, which inhibit HSV-1 replication in vitro with 50% effective concentration (EC50) values of 185, 118, and 60 μg/mL, respectively. For these extracts toxicity values were calculated and therefore selectivity indexes (SI) obtained. Further characterization of the bioactive components of antiviral plants will pave the way for the discovery of new compounds against HSV-1. PMID:22619617

  13. 18th International Conference on Antiviral Research.

    PubMed

    Mitchell, William M

    2005-08-01

    The 18th International Conference on Antiviral Research (ICAR) was held at the Princess Sofia Hotel in Barcelona, Spain, from 11th-14th April, 2005. This is a yearly international meeting sponsored by the International Society for Antiviral Research (ISAR). The current president of ISAR is John A Secrest 3rd of the Southern Research Institute. The scientific programme committee was chaired by John C Drach from the University of Michigan. ISAR was founded in 1987 to exchange prepublication basic, applied and clinical information on the development of antiviral, chemical and biological agents as well as to promote collaborative research. The ISAR has had a major role in the significant advances of the past decade in the reduction of the societal burdens of viral diseases by the focus of ICAR on the discovery and clinical application of antiviral agents. The 18th ICAR was organised as a series of focus presentations on specific viral groups consisting of oral and poster presentations of original research findings. In addition, the conference included plenary speakers, award presentations, a minisymposium on bioterrorism, and a satellite symposium on clinical antiviral drug developments. The size of the conference (> 50 oral and 250 poster presentations) necessitates limitation to the most noteworthy in the judgment of this reviewer. The current membership of the ISAR is approximately 700 with approximately 50% the membership in attendance.

  14. [Early onset pneumonia after successful resuscitation : Incidence after mild invasive hypothermia therapy].

    PubMed

    Erath, J W; Hodrius, J; Bushoven, P; Fichtlscherer, S; Zeiher, A M; Seeger, F H; Honold, J

    2017-09-01

    Targeted temperature management (TTM) represents an effective therapy to improve neurologic outcome in patients who survive an out-of-hospital cardiac arrest (OHCA). First publications about this therapy reported a higher incidence of infections in patients who underwent TTM induced by external cooling devices. Whether intravascular cooling devices are also associated with an increased infection rate has not been investigated so far. In a single center retrospective study, the incidence of early onset pneumonia (EOP) in OHCA patients with or without intravascular TTM at 33 °C target temperature for 24 h who survived at least 24 h after admission was analyzed. A total of 68 OHCA survivors (mean age 65 ± 15 years) were included in this analysis. The most common causes of OHCA were myocardial infarction (35 %), primary ventricular fibrillation (24 %), asystole (15 %), and pulmonary embolism (7 %). Of those, 32 patients (48 %) received TTM. The overall incidence of EOP was 38 %. Incidence of EOP did not differ significantly between groups, was more frequent in the group without TTM (42 % vs. 34 %, p = 0.57) and had no impact on mortality (hazard ratio = 1.02; 95 % confidence interval 0.25-4.16; p = 0.97). Intravascular TTM at 33 °C with a cooling catheter is not associated with more infective complications in OHCA patients. This finding underscores the safety of TTM.

  15. Systemic therapy for HER2-positive early-stage breast cancer.

    PubMed

    Mathew, Aju; Romond, Edward H

    The advent of the targeted monoclonal antbody trastuzumab for treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer marked a revolution in the understanding and management of mammary carcinoma and, in practice, separated this subtype from other kinds of primary breast malignancy. Long term follow-up from the initial large adjuvant trials continue to show remarkably positive results. Currently, at least four additional agents targeting this receptor, using different and complementary mechanisms of action compared with trastuzumab, have been incorporated into clinical trials. The small molecule tyrosine kinase inhibitors lapatinib and neratinib, in addition to the antibody pertuzumab and the antibody-drug conjugate trastuzumab-ematansine, have shown efficacy in metastatic breast cancer and are being evaluated both in neoadjuvant and adjuvant trials for early stage disease. The cytotoxic chemotherapy regimens used in combination with these agents also are evolving and different therapeutic approaches are emerging for patients depending on their relative level of risk from their cancers, thus moving clinical management toward individualized therapy. Much has been learned about managing the toxicities of treatment and pre-operative approaches have provided a means of assessing the sensitivity of individual patients' cancers to specific treatment regimens. This review traces the development of these studies and focuses on improvements in adjuvant and neoadjuvant therapy for patients with HER2-positive disease whose prognosis has changed in the last decade from dire to favorable. A path forward has been set by which the goal of cure is attainable for almost all patients faced with this aggressive form of breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities.

    PubMed

    Sgarbi, José A; Villaça, Fábio G; Garbeline, Benito; Villar, Heloísa E; Romaldini, João H

    2003-04-01

    Subclinical hyperthyroidism has been associated with harmful cardiac effects, but its treatment remains controversial. This study was designed to assess the cardiac effects of the normalization of serum TSH concentration in patients with endogenous subclinical hyperthyroidism. Ten patients (median age, 59 yr; range, 16-72 yr) with normal serum free T(4) and free T(3) concentration and a stable suppression of serum TSH levels were evaluated by Doppler-echocardiography, by standard and 24-h electrocardiography monitoring (Holter), and by the clinical Wayne index. Ten subjects, matched for age and sex, were used as controls. Patients were reevaluated 6 months after achieving stabilized euthyroidism by using methimazole with a median initial dose of 20 mg daily (10-30 mg daily). After reaching euthyroidism, we found a significant decrease in the heart rate (P = 0.008), the total number of beats during 24 h (P = 0.004), and the number of atrial (P = 0.002) and ventricular (P = 0.003) premature beats. Echocardiographical data resulted in a reduction of the left ventricular mass index (P = 0.009), interventricular septum thickness (P = 0.008), and left ventricular posterior wall thickness (P = 0.004) at diastole. Furthermore, the early diastolic peak flow velocity deceleration rate was significantly higher (P = 0.02) in the untreated patients compared with controls. The Wayne clinical index was higher in patients than in controls (P = 0.001) and decreased after treatment (P = 0.004). Serum TSH concentration returned to normal values after 2.5 months (range, 1.0-7.0 months) on methimazole therapy (0.05 vs. 1.42 mU/liter; P = 0.002). Serum free T(4) values were normal in patients before treatment but significantly decreased after reaching the euthyroidism (16.9 vs. 11.5 pmol/liter; P = 0.002). In contrast, serum free T(3) concentration did not differ among the groups. In conclusion, our findings support that early antithyroid therapy should be considered in patients with

  17. Symptom fluctuations, self-esteem, and cohesion during group cognitive behaviour therapy for early psychosis.

    PubMed

    Lecomte, Tania; Leclerc, Claude; Wykes, Til

    2018-03-01

    Group cohesion has been linked to positive changes in self-esteem and in symptoms during group psychotherapy in people with psychosis. These changes may be linked to changes in symptoms as fluctuations in self-esteem have been linked to symptom fluctuations. We aimed to determine the relationship between these three factors - group cohesion, self-esteem, and symptoms - during group cognitive behaviour therapy for psychosis (GCBTp). We hypothesized that group cohesion would precede changes in symptoms and self-esteem and that improvements in self-esteem would precede improvements in symptoms. This is an uncontrolled longitudinal study recruiting from a convenience sample within two early psychosis clinics. Sixty-six individuals from first episode of psychosis treatment programmes participated in this study and received 24 sessions of a validated GCBTp protocol. Participants answered a brief questionnaire at the end of each session, measuring their group cohesion, self-esteem, and perception of their symptoms as worse, same, or better than usual. Orthogonal polynomial contrasts for time effects were estimated with a mixed model for repeated measures with a random cluster effect and revealed a quartic trend regarding changes in symptoms over the 24 sessions. Self-esteem, symptoms, and group cohesion were strongly linked during a given session. Also, self-esteem changes predicted changes in symptoms up to two sessions later, and symptoms changes predicted self-esteem changes at the next session. Group cohesion preceded improvements in both self-esteem and symptoms; self-esteem also predicted improvements in group cohesion. These results suggest that self-esteem and symptoms influence each other during therapy, with improvements in one leading to improvements in the other. Group cohesion also appears to be an essential prerequisite to positive changes in self-esteem and symptoms during GCBTp. This study emphasizes the interrelation between self-esteem improvements and

  18. Heart protection by combination therapy with esmolol and milrinone at late-ischemia and early reperfusion.

    PubMed

    Huang, Ming-He; Wu, Yewen; Nguyen, Vincent; Rastogi, Saurabh; McConnell, Bradley K; Wijaya, Cori; Uretsky, Barry F; Poh, Kian-Keong; Tan, Huay-Cheem; Fujise, Kenichi

    2011-06-01

    The present study determined whether late-ischemia/early reperfusion therapy with the β(1)-adrenergic receptor (AR) blocker esmolol and phosphodiesterase III inhibitor milrinone reduced left ventricular (LV) myocardial infarct size (IS). In an ischemia/reperfusion rat model (30-min ischemia/4-hr reperfusion), esmolol, milrinone or esmolol + milrinone were intravenous (IV) infused over 10 min (from the last 5 min of ischemia to the first 5 min of reperfusion). LV-IS were 48.9 ± 8.9%, 41.5 ± 5.4%, 25.8 ± 7.7% and 16.8 ± 7.3% for saline, esmolol, milrinone, and esmolol + milrinone, respectively (n = 12/group). Esmolol + milrinone further reduced LV-IS compared with esmolol or milrinone alone (p < 0.05). LV-IS-reduction induced by esmolol + milrinone was eliminated in the presence of protein kinase A-(PKA)-inhibitor (Rp-cAMPS) or Akt-inhibitor (AKT 1/2 kinase inhibitor). In mixed rat ventricular cardiomyocyte cultures, intra-ischemic application of esmolol, milrinone or esmolol + milrinone reduced myocyte death rates by 5.5%, 13.3%, and 16.8%, respectively, compared with saline (p < 0.01). This cell protective effect by esmolol + milrinone was abrogated in the presence of PKA-inhibitor or Akt-inhibitor. Esmolol, milrinone or esmolol + milrinone increased myocardial PKA activity by 22%, 28% and 59%, respectively, compared with saline (n = 6, p < 0.01). No non-specific adverse effect of Rp-cAMPS on myocytes was identified in a purified myocyte preparation during hypoxia/re-oxygenation. Antiapoptotic pathways were assessed by measuring myocardial phosphorylated Akt (pAkt) levels combined with terminal dUTP nick-end labelling staining analysis. Ten minutes following infusion of esmolol, milrinone or esmolol + milrinone, there were 1.7-, 2.7-, and 6-fold increase in tissue pAkt levels, respectively. This esmolol + milrinone induced pAkt activation was abolished in the presence of PKA inhibitor. Esmolol, milrinone and esmolol + milrinone reduced myocyte apoptosis rates

  19. Effects of Cognitive Enhancement Therapy on Employment Outcomes in Early Schizophrenia: Results From a Two-Year Randomized Trial

    PubMed Central

    Eack, Shaun M.; Hogarty, Gerard E.; Greenwald, Deborah P.; Hogarty, Susan S.; Keshavan, Matcheri S.

    2013-01-01

    Objective To examine the effects of psychosocial cognitive rehabilitation on employment outcomes in a randomized controlled trial for individuals with early course schizophrenia. Method Early course schizophrenia outpatients (N = 58) were randomly assigned to Cognitive Enhancement Therapy (CET) or an Enriched Supportive Therapy (EST) control and treated for two years. Comprehensive data on cognition and employment were collected annually. Results Individuals treated with CET were significantly more likely to be competitively employed, had greater earnings from employment, and were more satisfied with their employment status by the end of treatment compared to EST recipients. Mediator analyses revealed that improvements in both social and non-social cognition mediated the CET effects on employment. Conclusion CET can help facilitate employment in early schizophrenia, by addressing the cognitive impairments that limit functioning in the disorder. Inclusion of cognitive rehabilitation in social work practice can support more optimal functional recovery from schizophrenia. PMID:23885163

  20. Biopsy Findings After Breast Conservation Therapy for Early-Stage Invasive Breast Cancer

    SciTech Connect

    Vapiwala, Neha; Starzyk, Jill; Harris, Eleanor E.

    2007-10-01

    Purpose: To determine the patterns and factors predictive of positive ipsilateral breast biopsy after conservation therapy for early-stage breast cancer. Methods and Materials: We performed a retrospective review of Stage I-II breast cancer patients initially treated with lumpectomy and radiotherapy between 1977 and 1996, who later underwent post-treatment ipsilateral breast biopsies. Results: A total of 223 biopsies were performed in 193 treated breasts: 171 single and 22 multiple biopsies. Of the 223 biopsies, 56% were positive and 44% were negative for recurrence. The positive biopsy rate (PBR) was 59% for the first and 32% for subsequent biopsies. The median timemore » to the first post-treatment biopsy was 49 months. Of the patients with negative initial biopsy findings, 11% later developed local recurrence. The PBR was 40% among patients with physical examination findings only, 65% with mammographic abnormalities only, and 79% with both findings (p = 0.001). Analysis of the procedure type revealed a PBR of 86% for core and 58% for excisional biopsies compared with 28% for aspiration cytology alone (p = 0.025). The PBR varied inversely with age at the original diagnosis: 49% if {>=}51 years, 57% if 36-50 years, and 83% if {<=}35 years (p = 0.05). The PBR correlated directly with the interval after radiotherapy: 49% if {<=}60 months, 59% if 60.1-120 months, 77% if 120.1-180 months, and 100% if >180 months after completing postlumpectomy radiotherapy (p = 0.01). The PBR was not linked with recurrence location, initial pathologic T or N stage, estrogen receptor/progesterone receptor status, or final pathologic margins (all p {>=} 0.15). Conclusion: After definitive radiotherapy for early-stage breast cancer, a greater PBR was associated with the presence of both mammographic and clinical abnormalities, excisional or core biopsies, younger age at the initial diagnosis, and longer intervals after radiotherapy completion.« less

  1. Effects of Antiretroviral Therapy on Autonomic Function in Early HIV Infection: A Preliminary Report

    PubMed Central

    Chow, Dominic; Kocher, Morgan; Shikuma, Cecilia; Parikh, Nisha; Grandinetti, Andrew; Nakamoto, Beau; Seto, Todd; Low, Phillip

    2012-01-01

    Background: A prospective study was conducted in human immunodeficiency virus (HIV)-infected patients as they undergo alterations in their antiretroviral therapy (ART) to determine the effect of ART on autonomic function. Methods: HIV-infected subjects who were either 1) naïve to ART and initiating ART, or 2) receiving ART and in HIV virologic failure for at least 4 months and were about to switch ART were enrolled in this study. Autonomic function assessment (cardiovagal, adrenergic, and sudomotor tests) was performed prior to and 4 months after initiating the new ART. Changes in clinical autonomic symptoms and virologic assessment were assessed. Results: Twelve subjects completed the study: 92% male; median age (Q1, Q3) was 41.0 (28.0, 48.2) years; and 50% White/Non-Hispanic. Seventy-five percent were ART naïve while 25% were failing their ART regimen. The median CD4 count was 336.5 (245.3, 372.3) cells/mm3. All subjects achieved an undetectable HIV viral load by the 4-month follow-up visit. The majority of naïve subjects were started on an ART regimen of tenofovir / emtricitabine / efavirenz. There were no significant differences in autonomic function assessment, as measured by cardiovagal, adrenergic, and sudomotor tests, with regards to ART initiation. Conclusion: This is the first study to examine the effects of initiating ART on autonomic function in early HIV infection. This study found no appreciable differences of ART on the autonomic nervous system when ART is initiated early in the course of HIV disease. ART may not contribute to short-term changes in autonomic function. PMID:22859899

  2. [Personalized cell therapy for early postoperative bullous keratopathy (experimental proof and clinical results)].

    PubMed

    Kasparov, A A; Kasparova, Evg A; Fadeeva, L L; Subbot, A M; Borodina, N V; Kasparova, E A; Kobzova, M V; Musaeva, G M; Pavliuk, A S

    2013-01-01

    The article presents the results of a long-term research on development and clinical application of personalized cell therapy (PCT) for treatment of early postoperative (manifesting within the first 3 months after surgery) bullous keratopathy (BK). The method of intracameral PCT implies in vitro incubation of the patient's blood sample with poly(A:U) stimulator, separation of the serum with activated leukocytes, and injection of the final cell preparation into the anterior chamber. The fundamental part of the research was aimed at a detailed description of the cell preparation and investigation of its possible mechanisms of action. Cytokine and growth factor level in the cell preparation suggested that its high clinical efficacy might be due to its ability to improve regeneration of damaged corneal endothelium. The clinical study was conducted on a group of 52 patients with early BK. A significant effect (smoothing of the Descement's membrane folds, complete resorption of corneal edema, improvement of corneal transparency, reduction of corneal thickness and increase of visual acuity by 0.49 +/- 0.27) was achieved in 44.2% of patients, while partial effect was seen in 21.1% of patients. There was no clinical effect in 34.6% of patients. In those patients who developed significant or partial clinical effect after the PCT, many endotheliocytes appeared to have multiple nuclei (2 and more). In some patients polyploid nuclei persisted for 3-5 years after the treatment. Polyploidy results from incomplete mitosis which might be due to regenerative processes in the endothelium stimulated by the PCT. Obviously, high efficacy and relative simplicity of the method should promote its further clinical introduction.

  3. Robot-assisted laparoscopic prostatectomy is not associated with early postoperative radiation therapy.

    PubMed

    Chino, Junzo; Schroeck, Florian R; Sun, Leon; Lee, W Robert; Albala, David M; Moul, Judd W; Koontz, Bridget F

    2009-11-01

    To compare open radical prostatectomy (RP) and robot-assisted laparoscopic prostatectomy (RALP), and to determine whether RALP is associated with a higher risk of features that determine recommendations for postoperative radiation therapy (RT). Patients undergoing RP from 2003 to 2007 were stratified into two groups: open RP and RALP. Preoperative (PSA level, T stage and Gleason score), pathological factors (T stage, Gleason score, extracapsular extension [ECE] and the status of surgical margins and seminal vesicle invasion [SVI]) and early treatment with RT or referral for RT within 6 months were compared between the groups. Multivariate analysis was used to control for selection bias in the RALP group. In all, 904 patients were identified; 368 underwent RALP and 536 underwent open RP (retropubic or perineal). Patients undergoing open RP had a higher pathological stage with ECE present in 24.8% vs 19.3% in RALP (P = 0.05) and SVI in 10.3% vs 3.8% (P < 0.001). In the RALP vs open RP group, there were positive surgical margins in 31.5% vs 31.9% (P = 0.9) and there were postoperative PSA levels of (3) 0.2 ng/mL in 5.7% vs 6.3% (P = 0.7), respectively. On multivariate analysis to control for selection bias, RALP was not associated with indication for RT (odds ratio (OR) 1.10, P = 0.55), or referral for RT (OR 1.04, P = 0.86). RALP was not associated with an increase in either indication or referral for early postoperative RT.

  4. Financial Implication of Radioactive Iodine Therapy for Early-Stage Papillary Thyroid Cancer.

    PubMed

    Al-Qurayshi, Zaid; Bu Ali, Daniah; Srivastav, Sudesh; Kandil, Emad

    2017-01-01

    The aim of this study was to evaluate disease-specific survival and cost related to radioactive iodine therapy (RAI) utilization in patients with early-stage papillary thyroid carcinoma (PTC). This was a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2012. A total of 38,374 patients with PTC were identified. Of those, 56.3% had adjuvant RAI. RAI administration was not associated with a survival advantage in patients with PTC stage I (hazard ratio [HR] 1.26, 95% confidence interval [CI] 0.11, 14.54; p = 0.85) or stage II (HR 0.50, 95% CI 0.05, 4.88; p = 0.55). Patients with PTC stage III who underwent adjuvant RAI had an improved survival (HR 0.30, 95% CI 0.10, 0.91; p = 0.033). In 2012, RAI was used in 45.5% of patients with stage I and in 71.4% of patients with stage II. The total expenditure on adjuvant RAI for PTC stage I throughout the study period was estimated to be USD 82.3 million with an annual average of USD 9.1 (±2.0) million/year. If the decline rate in the utilization of RAI continued, the model projected that the annual expenditure would decrease by USD 0.14 million/year. There is a high prevalence of adjuvant RAI utilization for early-stage PTC that is causing financial burden on the health system with no evidence of survival benefit. © 2017 S. Karger AG, Basel.

  5. A new early cognitive screening measure to detect cognitive side-effects of electroconvulsive therapy?

    PubMed

    Martin, Donel M; Katalinic, Natalie; Ingram, Anna; Schweitzer, Isaac; Smith, Deidre J; Hadzi-Pavlovic, Dusan; Loo, Colleen K

    2013-12-01

    Cognitive side-effects from electroconvulsive therapy (ECT) can be distressing for patients and early detection may have an important role in guiding treatment decisions over the ECT course. This prospective study examined the utility of an early cognitive screening battery for predicting cognitive side-effects which develop later in the ECT course. The screening battery, together with the Mini Mental Status Examination (MMSE), was administered to 123 patients at baseline and after 3 ECT treatments. A more detailed cognitive battery was administered at baseline, after six treatments (post ECT 6) and after the last ECT treatment (post treatment) to assess cognitive side-effects across several domains: global cognition, anterograde memory, executive function, speed and concentration, and retrograde memory. Multivariate analyses examined the predictive utility of change on items from the screening battery for later cognitive changes at post ECT 6 and post treatment. Results showed that changes on a combination of items from the screening battery were predictive of later cognitive changes at post treatment, particularly for anterograde memory (p < 0.01), after controlling for patient and treatment factors. Change on the MMSE predicted cognitive changes at post ECT 6 but not at post treatment. A scoring method for the new screening battery was tested for discriminative ability in a sub-sample of patients. This study provides preliminary evidence that a simple and easy-to-administer measure may potentially be used to help guide clinical treatment decisions to optimise efficacy and cognitive outcomes. Further development of this measure and validation in a more representative ECT clinical population is required. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Photodynamic therapy of early cancer in the upper aerodigestive tract and bronchi: instrumentation and clinical results

    NASA Astrophysics Data System (ADS)

    Wagnières, G.

    1990-01-01

    A complete instrumentation has been developed for photodynamic therapy (PDT) and combined PDT- hyperthermia in the upper aerodigestive tract and the bronchi. These instruments consist of several light distributors which permit optimal light dosage to "superficial" tumors, as well as an injector for laser beams into an optical fiber and a fiberoptic coupler for cw laser beam powers at least 100 Watts. PDT is carried out with HpD and Photofrin II at 630 nm, whereas occasional simultaneous hyperthermia is at 1.06 microns. PDT of 41 cases of "early" squamous cell carcinoma is reported with follow-up between 5 and 62 months. In the oesophagus and bronchi the results are good for cancers staged in situ or microinvasive at endoscopy (2 recurrences for 23 lesions treated). For more advanced cancers (submucosal in the oesopha- gus or invading the bronchial cartilage) the results are less satisfactory with 3 recurrences for 8 lesions treated. In the bronchi (1 case) and the oesophagus (1 case) the largest disease - free survival is now more than 5 years. We encountered 6 complications (3 cicatrical stenosis, 2 fistulae, 1 severe sunburn), most of them resulting from the lack of selectivity of PDT with these porphyrin mixtures at the applied conditions. These experiments show that PDT is efficient at destroying early squamous cell carcinomas in the pharynx, oesophagus and bronchi. Tumour selectivity of HpD and photofrin II is poor in the aerodigestive tract lined with squamous cell epithelium. The future lies in the synthesis of a more selective efficient photosensitizer.

  7. Early predictors of unresponsiveness to high-flow nasal cannula therapy in a pediatric emergency department.

    PubMed

    Er, Anıl; Çağlar, Aykut; Akgül, Fatma; Ulusoy, Emel; Çitlenbik, Hale; Yılmaz, Durgül; Duman, Murat

    2018-06-01

    High-flow nasal cannula (HFNC) is a new treatment option for pediatric respiratory distress and we aimed to assess early predictive factors of unresponsiveness to HFNC therapy in a pediatric emergency department (ED). Patients who presented with respiratory distress and were treated by HFNC, were included. The age, gender, weight, medical history, diagnosis, vital signs, oxygen saturation/fraction of inspired oxygen (SpO 2 /FiO 2 ) ratio, modified Respiratory Distress Assessment Instrument (mRDAI) scores, medical interventions, duration of HFNC therapy, time to escalation, adverse effects, and laboratory test results were obtained from medical and nursing records. The requirement of a higher level of respiratory support due to unchanged or increased RR compared to initial RR, incipient, or progressive respiratory acidosis, incipient hemodynamic instability was defined as unresponsiveness to HFNC. The study enrolled 154 children with a median age of 10 months (interquartile range [IQR], 5.7-22.5 months). The diagnosis was acute bronchiolitis in 59 patients (38.3%), bacterial pneumonia in 64 patients (41.6%), and atypical or viral pneumonia in 31 patients (20.1%). Twenty-five patients (16.2%) were in the unresponsive group, and the median time for escalating respiratory support was 7 h (IQR: 4-20 h). The unresponsive group had lower SpO 2 and SpO 2 /FiO 2 (SF) ratio on admission, lower venous pH, and higher partial pressure of carbon dioxide (pCO 2 ) (P = 0.002, P = 0.012, and P = 0.001, respectively). Also the alteration of RR, mRDAI score, and SF ratio at the first hour was greater in the responsive group. The cut-off value of SF ratio at the first hour of HFNC was 195 for unresponsiveness. The low initial SpO 2 and SF ratio, respiratory acidosis, and SF ratio less than 195 at the first hours of treatment were related to unresponsiveness to HFNC therapy in our pediatric emergency department. © 2018 Wiley Periodicals, Inc.

  8. Antiviral Activity of Polyacrylic and Polymethacrylic Acids

    PubMed Central

    De Somer, P.; De Clercq, E.; Billiau, A.; Schonne, E.; Claesen, M.

    1968-01-01

    Polyacrylic acid (PAA) and polymethacrylic acid (PMAA) were investigated for their antiviral properties in tissue culture. Compared to other related polyanions, as dextran sulfate, polystyrene sulfonate, polyvinyl sulfate, and polyphloroglucinol phosphate, PAA and PMAA were found to be significantly more antivirally active and less cytotoxic. PMAA added 24 hr prior to virus inoculation inhibited viral growth most efficiently but it was still effective when added 3 hr after infection. Neither a direct irreversible action on the virus nor inhibition of virus penetration into the cell could explain the antiviral activity of PMAA. PMAA inhibited the adsorption of the virus to the host cell and suppressed the one-cycle viral synthesis in tissue cultures inoculated with infectious RNA. PMID:4302187

  9. Antiviral Defense Mechanisms in Honey Bees

    PubMed Central

    Brutscher, Laura M.; Daughenbaugh, Katie F.; Flenniken, Michelle L.

    2015-01-01

    Honey bees are significant pollinators of agricultural crops and other important plant species. High annual losses of honey bee colonies in North America and in some parts of Europe have profound ecological and economic implications. Colony losses have been attributed to multiple factors including RNA viruses, thus understanding bee antiviral defense mechanisms may result in the development of strategies that mitigate colony losses. Honey bee antiviral defense mechanisms include RNA-interference, pathogen-associated molecular pattern (PAMP) triggered signal transduction cascades, and reactive oxygen species generation. However, the relative importance of these and other pathways is largely uncharacterized. Herein we review the current understanding of honey bee antiviral defense mechanisms and suggest important avenues for future investigation. PMID:26273564

  10. Innate and intrinsic antiviral immunity in Drosophila

    PubMed Central

    Mussabekova, Assel; Daeffler, Laurent; Imler, Jean-Luc

    2017-01-01

    The fruitfly Drosophila melanogaster has been a valuable model to investigate the genetic mechanisms of innate immunity. Initially focused on the resistance to bacteria and fungi, these studies have been extended to include antiviral immunity over the last decade. Like all living organisms, insects are continually exposed to viruses and have developed efficient defense mechanisms. We review here our current understanding on antiviral host-defense in fruit flies. A major antiviral defense in Drosophila is RNA interference, in particular the small interfering (si) RNA pathway. In addition, complex inducible responses and restriction factors contribute to the control of infections. Some of the genes involved in these pathways have been conserved through evolution, highlighting loci that may account for susceptibility to viral infections in humans. Other genes are not conserved and represent species-specific innovations. PMID:28102430

  11. Innate and intrinsic antiviral immunity in Drosophila.

    PubMed

    Mussabekova, Assel; Daeffler, Laurent; Imler, Jean-Luc

    2017-06-01

    The fruit fly Drosophila melanogaster has been a valuable model to investigate the genetic mechanisms of innate immunity. Initially focused on the resistance to bacteria and fungi, these studies have been extended to include antiviral immunity over the last decade. Like all living organisms, insects are continually exposed to viruses and have developed efficient defense mechanisms. We review here our current understanding on antiviral host defense in fruit flies. A major antiviral defense in Drosophila is RNA interference, in particular the small interfering (si) RNA pathway. In addition, complex inducible responses and restriction factors contribute to the control of infections. Some of the genes involved in these pathways have been conserved through evolution, highlighting loci that may account for susceptibility to viral infections in humans. Other genes are not conserved and represent species-specific innovations.

  12. Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection.

    PubMed

    Einsele, H; Hebart, H; Kauffmann-Schneider, C; Sinzger, C; Jahn, G; Bader, P; Klingebiel, T; Dietz, K; Löffler, J; Bokemeyer, C; Müller, C A; Kanz, L

    2000-04-01

    PCR-based preemptive therapy with ganciclovir has been shown to reduce the incidence of CMV disease after BMT. Failures of this treatment strategy are CMV disease and secondary non-viral infections. Eighty-six consecutive patients at high risk for CMV disease who received PCR-based preemptive therapy with ganciclovir were assessed for treatment failures and possible risk factors. Ganciclovir was initiated in 57 of 86 patients (66%). Only 28 of 86 (32%) patients received 4 or more weeks of ganciclovir. Recurrence of CMV infection after successful treatment was more frequent among recipients of a BMT from an unrelated compared to a sibling donor (P = 0.004). Three (3.5%) patients developed non-fatal early onset CMV disease and seven of 68 (10.3 %) late onset CMV disease (>100 days post transplant). Risk factors for late onset CMV disease were cGVHD (P = 0.0017) and duration of prior antiviral therapy >4 weeks (P = 0. 0073). The incidence of secondary non-viral infections was 28% with the duration of antiviral treatment being a significant risk factor for secondary bacterial (P = 0.0045) and invasive fungal infections (P = 0.006). Thus, PCR-based preemptive treatment with ganciclovir reduces early onset CMV disease, but the duration of antiviral therapy prior to day +100 is a significant risk factor for late onset CMV disease as well as secondary non-viral infections.

  13. Antiviral activity of formyl peptide receptor 2 antagonists against influenza viruses.

    PubMed

    Courtin, Noémie; Fotso, Aurélien Fotso; Fautrad, Pierre; Mas, Floriane; Alessi, Marie-Christine; Riteau, Béatrice

    2017-07-01

    Influenza viruses are one of the most important respiratory pathogens worldwide, causing both epidemic and pandemic infections. The aim of the study was to evaluate the effect of FPR2 antagonists PBP10 and BOC2 on influenza virus replication. We determined that these molecules exhibit antiviral effects against influenza A (H1N1, H3N2, H6N2) and B viruses. FPR2 antagonists used in combination with oseltamivir showed additive antiviral effects. Mechanistically, the antiviral effect of PBP10 and BOC2 is mediated through early inhibition of virus-induced ERK activation. Finally, our preclinical studies showed that FPR2 antagonists protected mice from lethal infections induced by influenza, both in a prophylactic and therapeutic manner. Thus, FPR2 antagonists might be explored for novel treatments against influenza. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Antiviral activity and specific modes of action of bacterial prodigiosin against Bombyx mori nucleopolyhedrovirus in vitro.

    PubMed

    Zhou, Wei; Zeng, Cheng; Liu, RenHua; Chen, Jie; Li, Ru; Wang, XinYan; Bai, WenWen; Liu, XiaoYuan; Xiang, TingTing; Zhang, Lin; Wan, YongJi

    2016-05-01

    Prodigiosin, the tripyrrole red pigment, is a bacterial secondary metabolite with multiple bioactivities; however, the antiviral activity has not been reported yet. In the present study, we found the antiviral activity of bacterial prodigiosin on Bombyx mori nucleopolyhedrovirus (BmNPV)-infected cells in vitro, with specific modes of action. Prodigiosin at nontoxic concentrations selectively killed virus-infected cells, inhibited viral gene transcription, especially viral early gene ie-1, and prevented virus-mediated membrane fusion. Under prodigiosin treatment, both progeny virus production and viral DNA replication were significantly inhibited. Fluorescent assays showed that prodigiosin predominantly located in cytoplasm which suggested it might interact with cytoplasm factors to inhibit virus replication. In conclusion, the present study clearly indicates that prodigiosin possesses significant antiviral activity against BmNPV.

  15. [Research Progress on Antiviral Activity of Interferon-induced Transmembrane Proteins].

    PubMed

    Chen, Yongkun; Zhu, Wenfei; Shu, Yuelong

    2016-03-01

    Interferon-induced Transmembrane Proteins (IFITMs) were identified through small interference RNA (siRNA) screening method in 1980s. The antiviral properties of the IFITMs were firstly discovered in 1996. Recently, its antiviral effect and mechanism have become a research hotspot. Many studies have shown that IFITM can inhibit the replication of multiple pathogenic viruses, including influenza A virus (IAV), Human Immunodeficiency Virus (HIV-1), hepatitis C virus (HCV), Ebola virus (EBOV), West Nile virus and so on. IFITMs inhibit the replication of virus in the early stage of the viral life cycle, which occurred before the release of viral genomes into the cytosol. Recent studies indicate that IFITM proteins could block viral replication by mediate viral membrane fusion. However, the mechanism is still under investigation. Here we review the discovery and characterization of the IFITM proteins, elucidate their antiviral activities and the potential mechanisms.

  16. Emotion recognition in early Parkinson's disease patients undergoing deep brain stimulation or dopaminergic therapy: a comparison to healthy participants.

    PubMed

    McIntosh, Lindsey G; Mannava, Sishir; Camalier, Corrie R; Folley, Bradley S; Albritton, Aaron; Konrad, Peter E; Charles, David; Park, Sohee; Neimat, Joseph S

    2014-01-01

    Parkinson's disease (PD) is traditionally regarded as a neurodegenerative movement disorder, however, nigrostriatal dopaminergic degeneration is also thought to disrupt non-motor loops connecting basal ganglia to areas in frontal cortex involved in cognition and emotion processing. PD patients are impaired on tests of emotion recognition, but it is difficult to disentangle this deficit from the more general cognitive dysfunction that frequently accompanies disease progression. Testing for emotion recognition deficits early in the disease course, prior to cognitive decline, better assesses the sensitivity of these non-motor corticobasal ganglia-thalamocortical loops involved in emotion processing to early degenerative change in basal ganglia circuits. In addition, contrasting this with a group of healthy aging individuals demonstrates changes in emotion processing specific to the degeneration of basal ganglia circuitry in PD. Early PD patients (EPD) were recruited from a randomized clinical trial testing the safety and tolerability of deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) in early-staged PD. EPD patients were previously randomized to receive optimal drug therapy only (ODT), or drug therapy plus STN-DBS (ODT + DBS). Matched healthy elderly controls (HEC) and young controls (HYC) also participated in this study. Participants completed two control tasks and three emotion recognition tests that varied in stimulus domain. EPD patients were impaired on all emotion recognition tasks compared to HEC. Neither therapy type (ODT or ODT + DBS) nor therapy state (ON/OFF) altered emotion recognition performance in this study. Finally, HEC were impaired on vocal emotion recognition relative to HYC, suggesting a decline related to healthy aging. This study supports the existence of impaired emotion recognition early in the PD course, implicating an early disruption of fronto-striatal loops mediating emotional function.

  17. Endoscopic treatment of early bronchial cancer: our experience with photodynamic therapy (PDT)

    NASA Astrophysics Data System (ADS)

    Corti, Luigi; Toniolo, Lamberto; Boso, Caterina; Colaut, Flavio; Fiore, Davide; Muzzio, Pier-Carlo; Loreggian, Lucio; Sotti, Guido

    2009-06-01

    The role of photodynamic therapy (PDT) in the treatment of small cancers has been established in several clinical studies. Here, we report on the efficacy of PDT for early inoperable or recurrent non-small-cell lung cancer (NSCLC). Methods and Materials: From June 1989 to November 2004, 40 patients with 50 NSCLC were treated with PDT. Twelve cases were inoperable for medical reasons and were staged as T1N0M0, and 28 had recurrent in situ carcinoma. Patients with residual disease after PDT received definitive radiotherapy and/or brachytherapy. Follow-up ranged from 6 to 167 months (median 43.59). Twenty of the 40 patients received i.v. injections of hematoporphyrin derivative (5 mg/kg), the other 20 had injections of porfimer sodium (Photofrin, 2 mg/kg). An argon dye laser (630 nm wavelength, 200-300 J/cm2) was used for light irradiation in 24 of the 40 patients, a diode laser (Diomed, 630 nm wavelength, 100- 200 J/cm2) in the other 16. Results: PDT obtained a 72% complete response (CR) rate (36/50 treated lesions), that is 27 CR among the 37 Tis carcinomas and 9 among the 13 T1 cases. Kaplan-Meier curves showed a mean overall survival (OS) of 75.59 months (median 91.4 months). Two- and 5- year OS rates were 72.78% and 59.55%. The mean and median survival rates for patients with Tis stage were 86.5 and 120.4 months, respectively (standard error 9.50) and for patients with T1 disease they were 45.78 and 35.71 months, respectively; the difference was statistically significant (P< 0.03). No severe early or late PDT-related adverse events were recorded. Conclusions: PDT is effective in early primary or recurrent NSCLC, resulting in a CR rate of 72%. The incorporation of PDT in standard clinical practice, in combination with radiotherapy, warrants further investigation.

  18. Oligonucleotides as antivirals: dream or realistic perspective?

    PubMed

    Van Aerschot, Arthur

    2006-09-01

    Many reports have been published on antiviral activity of synthetic oligonucleotides, targeted to act either by a true antisense effect or via non-sequence specific interactions. This short review will try to evaluate the current status of the field by focusing on the effects as reported for inhibition of either HSV-1, HCMV or HIV-1. Following an introduction with a historical background and a brief discussion on the different types of constructs and mechanisms of action, the therapeutic potential of antisense oligonucleotides as antivirals, as well as possible pitfalls upon their evaluation will be discussed.

  19. TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

    PubMed Central

    Zheng, Xiaojiao; Wang, Xinlu; Tu, Fan; Wang, Qin; Fan, Zusen

    2017-01-01

    ABSTRACT Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses by binding to viral mRNAs and repressing the translation and/or promoting the degradation of target mRNA. In addition, ZAP regulates the expression of certain cellular genes. Here, we report that tripartite motif-containing protein 25 (TRIM25), a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 abolished ZAP's antiviral activity. The E3 ligase activity of TRIM25 is required for this regulation. TRIM25 mediated ZAP ubiquitination, but the ubiquitination of ZAP itself did not seem to be required for its antiviral activity. Downregulation of endogenous ubiquitin or overexpression of the deubiquitinase OTUB1 impaired ZAP's activity. We provide evidence indicating that TRIM25 modulates the target RNA binding activity of ZAP. These results uncover a mechanism by which the antiviral activity of ZAP is regulated. IMPORTANCE ZAP is a host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1, Sindbis virus, and Ebola virus. ZAP binds directly to target mRNA, and it represses the translation and promotes the degradation of target mRNA. While the mechanisms by which ZAP posttranscriptionally inhibits target RNA expression have been extensively studied, how its antiviral activity is regulated is not very clear. Here, we report that TRIM25, a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 remarkably abolished ZAP's activity. TRIM25 is required for ZAP optimal binding to target mRNA. These results help us to better understand how the antiviral activity of ZAP is regulated. PMID:28202764

  20. TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein.

    PubMed

    Zheng, Xiaojiao; Wang, Xinlu; Tu, Fan; Wang, Qin; Fan, Zusen; Gao, Guangxia

    2017-05-01

    Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses by binding to viral mRNAs and repressing the translation and/or promoting the degradation of target mRNA. In addition, ZAP regulates the expression of certain cellular genes. Here, we report that tripartite motif-containing protein 25 (TRIM25), a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 abolished ZAP's antiviral activity. The E3 ligase activity of TRIM25 is required for this regulation. TRIM25 mediated ZAP ubiquitination, but the ubiquitination of ZAP itself did not seem to be required for its antiviral activity. Downregulation of endogenous ubiquitin or overexpression of the deubiquitinase OTUB1 impaired ZAP's activity. We provide evidence indicating that TRIM25 modulates the target RNA binding activity of ZAP. These results uncover a mechanism by which the antiviral activity of ZAP is regulated. IMPORTANCE ZAP is a host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1, Sindbis virus, and Ebola virus. ZAP binds directly to target mRNA, and it represses the translation and promotes the degradation of target mRNA. While the mechanisms by which ZAP posttranscriptionally inhibits target RNA expression have been extensively studied, how its antiviral activity is regulated is not very clear. Here, we report that TRIM25, a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 remarkably abolished ZAP's activity. TRIM25 is required for ZAP optimal binding to target mRNA. These results help us to better understand how the antiviral activity of ZAP is regulated. Copyright © 2017 American Society for Microbiology.

  1. Nanotheranostics: Emerging Strategies for Early Diagnosis and Therapy of Brain Cancer

    PubMed Central

    Sonali; Viswanadh, Matte Kasi; Singh, Rahul Pratap; Agrawal, Poornima; Mehata, Abhishesh Kumar; Pawde, Datta Maroti; Narendra; Sonkar, Roshan; Muthu, Madaswamy Sona

    2018-01-01

    Nanotheranostics have demonstrated the development of advanced platforms that can diagnose brain cancer at early stages, initiate first-line therapy, monitor it, and if needed, rapidly start subsequent treatments. In brain nanotheranostics, therapeutic as well as diagnostic entities are loaded in a single nanoplatform, which can be further developed as a clinical formulation for targeting various modes of brain cancer. In the present review, we concerned about theranostic nanosystems established till now in the research field. These include gold nanoparticles, carbon nanotubes, magnetic nanoparticles, mesoporous silica nanoparticles, quantum dots, polymeric nanoparticles, upconversion nanoparticles, polymeric micelles, solid lipid nanoparticles and dendrimers for the advanced detection and treatment of brain cancer with advanced features. Also, we included the role of three-dimensional models of the BBB and cancer stem cell concept for the advanced characterization of nanotheranostic systems for the unification of diagnosis and treatment of brain cancer. In future, brain nanotheranostics will be able to provide personalized treatment which can make brain cancer even remediable or at least treatable at the primary stages. PMID:29291164

  2. Breast cancer in the 21st century: from early detection to new therapies.

    PubMed

    Merino Bonilla, J A; Torres Tabanera, M; Ros Mendoza, L H

    The analysis of the causes that have given rise to a change in tendency in the incidence and mortality rates of breast cancer in the last few decades generates important revelations regarding the role of breast screening, the regular application of adjuvant therapies and the change of risk factors. The benefits of early detection have been accompanied by certain adverse effects, even in terms of an excessive number of prophylactic mastectomies. Recently, several updates have been published on the recommendations in breast cancer screening at an international level. On the other hand, the advances in genomics have made it possible to establish a new molecular classification of breast cancer. Our aim is to present an updated overview of the epidemiological situation of breast cancer, as well as some relevant issues from the point of view of diagnosis, such as molecular classification and different strategies for both population-based and opportunistic screening. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Impact of Early Initiation of Antiretroviral Therapy in Patients with Acute HIV Infection in Vienna, Austria

    PubMed Central

    Herout, Sandra; Mandorfer, Mattias; Breitenecker, Florian; Reiberger, Thomas; Grabmeier-Pfistershammer, Katharina; Rieger, Armin; Aichelburg, Maximilian C.

    2016-01-01

    Background It is unclear whether antiretroviral therapy (ART) should be initiated during acute HIV infection. Most recent data provides evidence of benefits of early ART. Methods We retrospectively compared the clinical and immunological course of individuals with acute HIV infection, who received ART within 3 months (group A) or not (group B) after diagnosis. Results Among the 84 individuals with acute HIV infection, 57 (68%) received ART within 3 months (A) whereas 27 (32%) did not receive ART within 3 months (B), respectively. Clinical progression to CDC stadium B or C within 5 years after the diagnosis of HIV was less common in (A) when compared to (B) (P = 0.002). After twelve months, both the mean increase in CD4+ T cell count and the mean decrease in viral load was more pronounced in (A), when compared to (B) (225 vs. 87 cells/μl; P = 0.002 and -4.19 vs. -1.14 log10 copies/mL; P<0.001). Twenty-four months after diagnosis the mean increase from baseline of CD4+ T cells was still higher in group A compared to group B (251 vs. 67 cells/μl, P = 0.004). Conclusions Initiation of ART during acute HIV infection is associated with a lower probability of clinical progression to more advanced CDC stages and significant immunological benefits. PMID:27065239

  4. Variations in locoregional therapy in postmenopausal patients with early breast cancer treated in different countries.

    PubMed

    van Nes, J G H; Seynaeve, C; Jones, S; Markopoulos, C; Putter, H; van de Velde, C J H; Hasenburg, A; Rea, D W; Vannetzel, J-M; Dirix, L; Hozumi, Y; Kerin, M J; Kieback, D G; Meershoek-Klein Kranenbarg, W M; Hille, E T M; Nortier, J W R

    2010-05-01

    The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial is an international randomized trial evaluating the efficacy and safety of exemestane, alone or following tamoxifen. The large number of patients already recruited offered the opportunity to explore locoregional treatment practices between countries. Patients were enrolled in Belgium, France, Germany, Greece, Ireland, Japan, the Netherlands, the UK and the USA. The core protocol had minor differences in eligibility criteria between countries, reflecting variations in national guidelines and practice regarding adjuvant endocrine therapy. Between 2001 and 2006, 9779 patients of mean(s.d.) age 64(9) years were randomized. Some 58.4 per cent had T1 tumours (range between countries 36.8-75.9 per cent; P < 0.001) and 47.3 per cent were axillary node positive (range 25.9-84.6 per cent; P < 0.001). Independent factors for type of breast surgery were country, age, tumour status and calendar year of surgery. After breast-conserving surgery, radiotherapy was given to 93.2 per cent of patients, 86.0 per cent in the USA and 100 per cent in France. Axillary lymph node dissection was performed in 82.0 (range 74.6-99.1) per cent. Despite international consensus guidelines, wide global variations were observed in treatment practices of early breast cancer. There should be further efforts to optimize locoregional treatment for breast cancer worldwide. Copyright 2010 British Journal of Surgery Society Ltd.

  5. Results and survival after photodynamic therapy in early-stage esophageal carcinoma

    NASA Astrophysics Data System (ADS)

    Spinelli, Pasquale; Mancini, Andrea; Dal Fante, Marco; Meroni, Emmanuele; Jasinskas, Algirdas

    1996-01-01

    From January 1985 to December 1994, 23 early stage carcinomas of the esophagus were treated by photodynamic therapy in 21 patients. The stage of the tumors was assessed by esophagoscopy with multiple biopsies, CT scan and, from June 1991, also by endoscopic ultrasonography: 7 lesions were classified as carcinoma in situ (Tis) and 16 as invasive (T1). The photosensitizers used for PDT were hematoporphyrin derivative 3 mg/kg in 4 patients and dihematoporphyrin ether 2 mg/kg in 17. Light irradiation was performed using an Argon-dye laser system at a wavelength of 630 nm with an average energy of 50 J/cm2 and 70 J/cm2 for the treatment of Tis and T1, respectively. A complete response was achieved in 17/23 (74%) tumors, 15/21 (71%) patients. In the follow-up period from 6 to 78 months (median 36 months) 3 recurrences occurred 6, 12, and 14 months after PDT, respectively. Seven patients died due to concomitant diseases, not related to tumor progression. The actuarial survival rate was 95%, 75% and 37% at 1, 3, and 5 years, respectively. Complications included 1 case of sunburn and 2 cases of esophageal stenosis at the treatment site, that gradually responded to endoscopic bougienage.

  6. Early antiretroviral therapy and potent second-line drugs could decrease HIV incidence of drug resistance.

    PubMed

    Shen, Mingwang; Xiao, Yanni; Rong, Libin; Meyers, Lauren Ancel; Bellan, Steven E

    2017-06-28

    Early initiation of antiretroviral therapy (ART) reduces the risk of drug-sensitive HIV transmission but may increase the transmission of drug-resistant HIV. We used a mathematical model to estimate the long-term population-level benefits of ART and determine the scenarios under which earlier ART (treatment at 1 year post-infection, on average) could decrease simultaneously both total and drug-resistant HIV incidence (new infections). We constructed an infection-age-structured mathematical model that tracked the transmission rates over the course of infection and modelled the patients' life expectancy as a function of ART initiation timing. We fitted this model to the annual AIDS incidence and death data directly, and to resistance data and demographic data indirectly among men who have sex with men (MSM) in San Francisco. Using counterfactual scenarios, we assessed the impact on total and drug-resistant HIV incidence of ART initiation timing, frequency of acquired drug resistance, and second-line drug effectiveness (defined as the combination of resistance monitoring, biomedical drug efficacy and adherence). Earlier ART initiation could decrease the number of both total and drug-resistant HIV incidence when second-line drug effectiveness is sufficiently high (greater than 80%), but increase the proportion of new infections that are drug resistant. Thus, resistance may paradoxically appear to be increasing while actually decreasing. © 2017 The Author(s).

  7. Assessment of an intervention aimed at early discontinuation of intravenous antimicrobial therapy in a Brazilian University hospital.

    PubMed

    Bonella, Gislaine Ferraresi; Fontes, Astrídia Marília de Souza; Jorge, Miguel Tanús; Silveira, Alexandre Barcelos Morais da

    2016-01-01

    Many interventions demonstrate success in adapting the duration of intravenous antibiotic therapy, but few studies have been conducted in developing countries. The aim of this study was to evaluate the effectiveness of an intervention in the induction of early discontinuation of intravenous antimicrobial therapy and/or its switch to oral therapy. The study employed a before-after intervention design that consisted of displaying a message in the computerized prescription on the third day and suspension of the prescription on the fifth day of intravenous antimicrobial therapy. A total of 465 patients were followed during the control period (CP) and 440 in the intervention period (IP). The intravenous therapy was switched to oral therapy for 11 (2.4%) patients during the CP and 25 (5.7%) in the IP (p=0.011), and was discontinued for 82 (17.6%) patients during the CP and 106 (24.1%) in the IP (p=0.017). During the IP there was a significant increase of patients who had their antimicrobial treatment discontinued before the seventh day of intravenous treatment, 37.40% (49/131) in the IP and 16.13% (15/93) in the CP (p=0.0005). The duration of intravenous antimicrobial therapy decreased by one day, but it was not significant (p=0.136). It is concluded that the proposed intervention is effective in promoting the early discontinuation of antimicrobial treatment and/or switch to oral therapy. As long as a computerized system for prescription already exists, it is easy and inexpensive to be implemented, especially in hospitals in developing countries. Copyright © 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.

  8. Perfusion MDCT enables early detection of therapeutic response to antiangiogenic therapy.

    PubMed

    Sabir, Adeel; Schor-Bardach, Rachel; Wilcox, Carol J; Rahmanuddin, Syed; Atkins, Michael B; Kruskal, Jonathan B; Signoretti, Sabina; Raptopoulos, Vassilios D; Goldberg, S Nahum

    2008-07-01

    The objective of our study was to determine whether perfusion CT can be used to detect early changes in therapeutic response to antiangiogenic therapy in an animal tumor model. Twenty-five rats implanted with R3230 mammary adenocarcinoma (diameter, 1.2-2.0 cm) randomly received 7.5 or 30 mg/kg of an antiangiogenic agent, sorafenib, by daily gavage for 4 (n = 4), 9 (n = 9), or 14 (n = 5) days. Seven untreated animals served as a control group. Perfusion MDCT was performed at days 0, 4, 9, and 14 with 0.4 mL of ioversol (350 mg/mL) and included four 5-mm slices covering the entire tumor volume. Changes in tumor growth were determined by volumetric analysis of CT data. Serial changes in tumor volume and blood flow were assessed and correlated with pathology findings. All control tumors grew larger (from 2.0 +/- 0.7 cm(3) at day 0 to 5.9 +/- 1.0 cm(3) at day 14), whereas all treated tumors shrank (from 2.5 +/- 1.1 to 2.1 +/- 1.0 cm(3)), with a statistically significant rate of growth or shrinkage in both groups (p < 0.05). Although perfusion in the control tumors changed little from day 0 to day 14 (day 0, 18.1 +/- 9.2 mL/min/100 g; day 4, 15.8 +/- 5.6; day 9, 21.7 +/- 12.2; day 14, 27.7 +/- 34), in the sorafenib group, the mean blood flow was significantly lower at day 4 (5.2 +/- 3.2 mL/min/100 g, 77% decrease), day 9 (6.4 +/- 4.0 mL/min/100 g, 66% decrease), and day 14 (6.3 +/- 5.2 mL/min/100 g, 83% decrease) compared with day 0 (23.8 +/- 11.6 mL/min/100 g) (p < 0.05). Poor correlation was seen between changes in blood flow and tumor volume for days 0-9 (r(2) = 0.34), 4-9 (r(2) = 0.0004), and 9-14 (r(2) = 0.16). However, when comparing day 4 images with days 9 and 14 images, seven of 14 (50%) sorafenib-treated tumors had focal areas of new perfusion that correlated with areas of histopathologic viability despite the fact that these tumors were shrinking in size from day 4 onward (day 4, 2.18 +/- 0.8 cm(3); day 9, 1.98 +/- 0.8 cm(3)). Perfusion MDCT can detect focal

  9. Antiviral Effects of Saffron and its Major Ingredients.

    PubMed

    Soleymani, Sepehr; Zabihollahi, Rezvan; Shahbazi, Sepideh; Bolhassani, Azam

    2018-01-01

    The lack of an effective vaccine against viral infections, toxicity of the synthetic anti-viral drugs and the generation of resistant viral strains led to discover novel inhibitors. Recently, saffron and its compounds were used to treat different pathological conditions. In this study, we tested the anti-HSV-1 and anti-HIV-1 activities of Iranian saffron extract and its major ingredients including crocin and picrocrocin as well as cytotoxicity in vitro. The data showed that the aqueous saffron extract was not active against HIV-1 and HSV-1 virions at certain doses (i.e., a mild activity), but crocin and picrocrocin indicated significant anti-HSV-1 and also anti-HIV-1 activities. Crocin inhibited the HSV replication at before and after entry of virions into Vero cells. Indeed, crocin carotenoid suppressed HSV penetration in the target cells as well as disturbed virus replication after entry into the cells. Picrocrocin was also effective for inhibiting virus entry and also its replication. This monoterpen aldehyde showed higher anti-HSV effects after virus penetrating in the cells. Generally, these sugar-containing compounds extracted from saffron showed to be effective antiherpetic drug candidates. The recent study is the first report suggesting antiviral activities for saffron extract and its major ingredients. Crocin and picrocrocin could be a promising anti-HSV and anti-HIV agent for herbal therapy against viral infections. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. ZFP36 RNA-binding proteins restrain T-cell activation and anti-viral immunity.

    PubMed

    Moore, Michael J; Blachere, Nathalie E; Fak, John J; Park, Christopher Y; Sawicka, Kirsty; Parveen, Salina; Zucker-Scharff, Ilana; Moltedo, Bruno; Rudensky, Alexander Y; Darnell, Robert B

    2018-05-31

    Dynamic post-transcriptional control of RNA expression by RNA-binding proteins (RBPs) is critical during immune response. ZFP36 RBPs are prominent inflammatory regulators linked to autoimmunity and cancer, but functions in adaptive immunity are less clear. We used HITS-CLIP to define ZFP36 targets in mouse T cells, revealing unanticipated actions in regulating T cell activation, proliferation, and effector functions. Transcriptome and ribosome profiling showed that ZFP36 represses mRNA target abundance and translation, notably through novel AU-rich sites in coding sequence. Functional studies revealed that ZFP36 regulates early T cell activation kinetics cell autonomously, by attenuating activation marker expression, limiting T cell expansion, and promoting apoptosis. Strikingly, loss of ZFP36 in vivo accelerated T cell responses to acute viral infection and enhanced anti-viral immunity. These findings uncover a critical role for ZFP36 RBPs in restraining T cell expansion and effector functions, and suggest ZFP36 inhibition as a strategy to enhance immune-based therapies. © 2018, Moore et al.

  11. Evaluation of early antimicrobial therapy adaptation guided by the BetaLACTA® test: a case-control study.

    PubMed

    Garnier, Marc; Rozencwajg, Sacha; Pham, Tài; Vimont, Sophie; Blayau, Clarisse; Hafiani, Mehdi; Fulgencio, Jean-Pierre; Bonnet, Francis; Mainardi, Jean-Luc; Arlet, Guillaume; Fartoukh, Muriel; Gallah, Salah; Quesnel, Christophe

    2017-06-28

    Rapid diagnostic tests detecting microbial resistance are needed for limiting the duration of inappropriateness of empirical antimicrobial therapy (EAT) in intensive care unit patients, besides reducing the use of broad-spectrum antibiotics. We hypothesized that the betaLACTA® test (BLT) could lead to early increase in the adequacy of antimicrobial therapy. This was a case-control study. Sixty-one patients with BLT-guided adaptation of EAT were prospectively included, and then matched with 61 "controls" having similar infection characteristics (community or hospital-acquired, and source of infection), in whom EAT was conventionally adapted to antibiogram results. Endpoints were to compare the proportion of appropriate (primary endpoint) and optimal (secondary endpoint) antimicrobial therapies with each of the two strategies, once microbiological sample culture results were available. Characteristics of patients, infections and EAT at inclusion were similar between groups. Nine early escalations of EAT occurred in the BLT-guided adaptation group, reaching 98% appropriateness vs. 77% in the conventional adaptation group (p < 0.01). The BLT reduced the time until escalation of an inappropriate EAT from 50.5 (48-73) to 27 (24-28) hours (p < 0.01). Seventeen early de-escalations occurred in the BLT-guided adaptation group, compared to one in the conventional adaptation group, reducing patients' exposure to broad-spectrum beta-lactam such as carbapenems. In multivariate analysis, use of the BLT was strongly associated with early appropriate (OR = 18 (3.4-333.8), p = 0.006) and optimal (OR = 35.5 (9.6-231.9), p < 0.001) antimicrobial therapies. Safety parameters were similar between groups. Our study suggests that a BLT-guided adaptation strategy may allow early beta-lactam adaptation from the first 24 hours following the beginning of sepsis management.

  12. Psychological morbidities in adolescent and young adult blood cancer patients during curative-intent therapy and early survivorship.

    PubMed

    Muffly, Lori S; Hlubocky, Fay J; Khan, Niloufer; Wroblewski, Kristen; Breitenbach, Katherine; Gomez, Joseline; McNeer, Jennifer L; Stock, Wendy; Daugherty, Christopher K

    2016-03-15

    Adolescents and young adults (AYAs) with cancer face unique psychosocial challenges. This pilot study was aimed at describing the prevalence of psychological morbidities among AYAs with hematologic malignancies during curative-intent therapy and early survivorship and at examining provider perceptions of psychological morbidities in their AYA patients. Patients aged 15 to 39 years with acute leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma who were undergoing curative-intent therapy (on-treatment group) or were in remission within 2 years of therapy completion (early survivors) underwent a semistructured interview that incorporated measures of anxiety, depression, and posttraumatic stress (PTS). A subset of providers (n = 15) concomitantly completed a survey for each of the first 30 patients enrolled that evaluated their perception of each subject's anxiety, depression, and PTS. Sixty-one of 77 eligible AYAs participated. The median age at diagnosis was 26 years (range, 15-39 years), 64% were male, and 59% were non-Hispanic white. On-treatment demographics differed significantly from early-survivor demographics only in the median time from diagnosis to interview. Among the 61 evaluable AYAs, 23% met the criteria for anxiety, 28% met the criteria for depression, and 13% met the criteria for PTS; 46% demonstrated PTS symptomatology. Thirty-nine percent were impaired in 1 or more psychological domains. Psychological impairments were as frequent among early survivors as AYAs on treatment. Provider perceptions did not significantly correlate with patient survey results. AYAs with hematologic malignancies experience substantial psychological morbidities while they are undergoing therapy and during early survivorship, with more than one-third of the patients included in this study meeting the criteria for anxiety, depression, or traumatic stress. This psychological burden may not be accurately identified by their oncology providers. © 2016 American Cancer Society.

  13. Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis.

    PubMed

    Rowan, Kathryn M; Angus, Derek C; Bailey, Michael; Barnato, Amber E; Bellomo, Rinaldo; Canter, Ruth R; Coats, Timothy J; Delaney, Anthony; Gimbel, Elizabeth; Grieve, Richard D; Harrison, David A; Higgins, Alisa M; Howe, Belinda; Huang, David T; Kellum, John A; Mouncey, Paul R; Music, Edvin; Peake, Sandra L; Pike, Francis; Reade, Michael C; Sadique, M Zia; Singer, Mervyn; Yealy, Donald M

    2017-06-08

    After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and

  14. Aspirin and Statin Nonuse Associated With Early Biochemical Failure After Prostate Radiation Therapy

    SciTech Connect

    Zaorsky, Nicholas G.; Buyyounouski, Mark K., E-mail: mark.buyyounouski@fccc.edu; Li, Tianyu

    Purpose: To present the largest retrospective series investigating the effect of aspirin and statins, which are hypothesized to have antineoplastic properties, on biochemical failure (nadir plus 2 ng/mL) after prostate radiation therapy (RT). Methods and Materials: Between 1989 and 2006, 2051 men with clinically localized prostate cancer received definitive RT alone (median dose, 76 Gy). The rates of aspirin use and statin use (defined as any use at the time of RT or during follow-up) were 36% and 34%, respectively. The primary endpoint of the study was an interval to biochemical failure (IBF) of less than 18 months, which hasmore » been shown to be the single strongest predictor of distant metastasis, prostate cancer survival, and overall survival after RT. Patient demographic characteristics and tumor staging factors were assessed with regard to associations with the endpoint. Univariate analysis was performed with the {chi}{sup 2} test for categorical variables and the Wilcoxon test for continuous variables. Multivariable analysis was performed with a multiple logistic regression. Results: The median follow-up was 75 months. Univariate analysis showed that an IBF of less than 18 months was associated with aspirin nonuse (P<.0001), statin nonuse (P<.0001), anticoagulant nonuse (P=.0006), cardiovascular disease (P=.0008), and prostate-specific antigen (continuous) (P=.008) but not with Gleason score, age, RT dose, or T stage. On multivariate analysis, only aspirin nonuse (P=.0012; odds ratio, 2.052 [95% confidence interval, 1.328-3.172]) and statin nonuse (P=.0002; odds ratio, 2.465 [95% confidence interval, 1.529-3.974]) were associated with an IBF of less than 18 months. Conclusions: In patients who received RT for prostate cancer, aspirin or statin nonuse was associated with early biochemical failure, a harbinger of distant metastasis and death. Further study is needed to confirm these findings and to determine the optimal dosing and schedule, as well as the

  15. Predictors of receiving therapy among very low birth weight 2-year olds eligible for Part C early intervention in Wisconsin.

    PubMed

    McManus, Beth Marie; Robert, Stephanie; Albanese, Aggie; Sadek-Badawi, Mona; Palta, Mari

    2013-07-11

    The Individuals with Disabilities Education Act (Part C) authorizes states to establish systems to provide early intervention services (e.g., therapy) for children at risk, with the incentive of federal financial support. This study examines family and neighborhood characteristics associated with currently utilizing physical, occupational, or speech therapy among very low birthweight (VLBW) 2-year-old children who meet Wisconsin eligibility requirements for early intervention services (EI) due to developmental delay. This cross-sectional analysis used data from the Newborn Lung Project, a regional cohort study of VLBW infants hospitalized in Wisconsin's newborn intensive care units during 2003-2004. We included the 176 children who were age two at follow-up, and met Wisconsin state eligibility requirements for EI based on developmental delay. Exact logistic regression was used to describe child and neighborhood socio-demographic correlates of parent-reported receipt of therapy. Among VLBW children with developmental delay, currently utilizing therapy was higher among children with Medicaid (aOR = 5.3, 95% CI: 1.3, 28.3) and concomitant developmental disability (aOR = 5.2, 95% CI: 2.1, 13.3) and lower for those living in a socially more disadvantaged neighborhood (aOR=0.48, 95% CI: 0.21, 0.98, per tertile). Among a sample of VLBW 2-year olds with developmental delays who are EI-eligible in WI, 4 out of 5 were currently receiving therapy, per parent report. Participation in Medicaid positively influences therapy utilization. Children with developmental difficulties who live in socially disadvantaged neighborhoods are at highest risk for not receiving therapy.

  16. Early blood pressure, anti-hypotensive therapy and outcomes at 18 to 22 month corrected age in extremely preterm infants

    PubMed Central

    Batton, Beau; Li, Lei; Newman, Nancy S.; Das, Abhik; Watterberg, Kristi L.; Yoder, Bradley A.; Faix, Roger G.; Laughon, Matthew M.; Stoll, Barbara J.; Higgins, Rosemary D.; Walsh, Michele C.

    2016-01-01

    Objective Investigate relationships between early blood pressure (BP) changes, receipt of anti-hypotensive therapy, and 18 – 22 month corrected age (CA) outcomes for extremely preterm infants. Design Prospective observational study of infants 230/7 – 266/7 weeks gestational age (GA). Hourly BP values and anti-hypotensive therapy exposure in the first 24 hours were recorded. Four groups were defined: infants who did or did not receive anti-hypotensive therapy in whom BP did or did not rise at the expected rate (defined as an increase in the mean arterial BP of ≥5 mmHg/day). Random-intercept logistic modeling controlling for center clustering, GA, and illness severity was used to investigate the relationship between BP, anti-hypotensive therapies, and infant outcomes. Setting Sixteen academic centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Main Outcome Measures Death or neurodevelopmental impairment / developmental delay (NIDD) at 18 – 22 months CA. Results Of 367 infants, 203 (55%) received an anti-hypotensive therapy, 272 (74%) survived to discharge, and 331 (90%) had a known outcome at 18 – 22 months CA. With logistic regression, there was an increased risk of death/NIDD with anti-hypotensive therapy versus no treatment (odds ratio: 1.836, 95% confidence interval: 1.092 – 3.086), but not NIDD alone (odds ratio: 1.53, 95% confidence interval: 0.708 – 3.307). Conclusion Independent of early BP changes, anti-hypotensive therapy exposure was associated with an increased risk of death/NIDD at 18 to 22 months CA when controlling for risk factors known to affect survival and neurodevelopment. PMID:26567120

  17. Predictors of receiving therapy among very low birth weight 2-year olds eligible for Part C early intervention in Wisconsin

    PubMed Central

    2013-01-01

    Background The Individuals with Disabilities Education Act (Part C) authorizes states to establish systems to provide early intervention services (e.g., therapy) for children at risk, with the incentive of federal financial support. This study examines family and neighborhood characteristics associated with currently utilizing physical, occupational, or speech therapy among very low birthweight (VLBW) 2-year-old children who meet Wisconsin eligibility requirements for early intervention services (EI) due to developmental delay. Methods This cross-sectional analysis used data from the Newborn Lung Project, a regional cohort study of VLBW infants hospitalized in Wisconsin’s newborn intensive care units during 2003–2004. We included the 176 children who were age two at follow-up, and met Wisconsin state eligibility requirements for EI based on developmental delay. Exact logistic regression was used to describe child and neighborhood socio-demographic correlates of parent-reported receipt of therapy. Results Among VLBW children with developmental delay, currently utilizing therapy was higher among children with Medicaid (aOR = 5.3, 95% CI: 1.3, 28.3) and concomitant developmental disability (aOR = 5.2, 95% CI: 2.1, 13.3) and lower for those living in a socially more disadvantaged neighborhood (aOR=0.48, 95% CI: 0.21, 0.98, per tertile). Conclusions Among a sample of VLBW 2-year olds with developmental delays who are EI-eligible in WI, 4 out of 5 were currently receiving therapy, per parent report. Participation in Medicaid positively influences therapy utilization. Children with developmental difficulties who live in socially disadvantaged neighborhoods are at highest risk for not receiving therapy. PMID:23845161

  18. Computerised mirror therapy with Augmented Reflection Technology for early stroke rehabilitation: clinical feasibility and integration as an adjunct therapy.

    PubMed

    Hoermann, Simon; Ferreira Dos Santos, Luara; Morkisch, Nadine; Jettkowski, Katrin; Sillis, Moran; Devan, Hemakumar; Kanagasabai, Parimala S; Schmidt, Henning; Krüger, Jörg; Dohle, Christian; Regenbrecht, Holger; Hale, Leigh; Cutfield, Nicholas J

    2017-07-01

    New rehabilitation strategies for post-stroke upper limb rehabilitation employing visual stimulation show promising results, however, cost-efficient and clinically feasible ways to provide these interventions are still lacking. An integral step is to translate recent technological advances, such as in virtual and augmented reality, into therapeutic practice to improve outcomes for patients. This requires research on the adaptation of the technology for clinical use as well as on the appropriate guidelines and protocols for sustainable integration into therapeutic routines. Here, we present and evaluate a novel and affordable augmented reality system (Augmented Reflection Technology, ART) in combination with a validated mirror therapy protocol for upper limb rehabilitation after stroke. We evaluated components of the therapeutic intervention, from the patients' and the therapists' points of view in a clinical feasibility study at a rehabilitation centre. We also assessed the integration of ART as an adjunct therapy for the clinical rehabilitation of subacute patients at two different hospitals. The results showed that the combination and application of the Berlin Protocol for Mirror Therapy together with ART was feasible for clinical use. This combination was integrated into the therapeutic plan of subacute stroke patients at the two clinical locations where the second part of this research was conducted. Our findings pave the way for using technology to provide mirror therapy in clinical settings and show potential for the more effective use of inpatient time and enhanced recoveries for patients. Implications for Rehabilitation Computerised Mirror Therapy is feasible for clinical use Augmented Reflection Technology can be integrated as an adjunctive therapeutic intervention for subacute stroke patients in an inpatient setting Virtual Rehabilitation devices such as Augmented Reflection Technology have considerable potential to enhance stroke rehabilitation.

  19. Targeted vs. systematic early antiviral treatment against A(H1N1)v influenza with neuraminidase inhibitors in patients with influenza-like symptoms: Clinical and economic impact

    PubMed Central

    Deuffic-Burban, Sylvie; Lenne, Xavier; Dervaux, Benoit; Julien Poissy; Lemaire, Xavier; Sloan, Caroline; Carrat, Fabrice; Desenclos, Jean-Claude; Delfraissy, Jean-Francois; Yazdanpanah, Yazdan

    2009-01-01

    Capitalizing on available data, we used a decision model to estimate the clinical and economic outcomes associated with early initiation of treatment with neuraminidase inhibitors in all patients with influenza-like illnesses ( ILI ) (systematic strategy) vs. only those at high risk of complications (targeted strategy). Systematic treatment of ILI during an A(H1N1)v influenza epidemic wave is both effective and cost-effective. Patients who present to care with ILI during an A(H1N1)v influenza epidemic wave should initiate treatment with neuraminidase inhibitors, regardless of risk status. Administering neuraminidase inhibitors between epidemic waves, when the probability of influenza is low, is less effective and cost-effective. PMID:20029659

  20. Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia

    PubMed Central

    Sarrazy, Vincent; Dumas, Karine; Authier, Florence; Sore, Sophie; Tran, Albert; Gual, Philippe; Gennero, Isabelle; Salles, Jean-Pierre; Gouze, Elvire

    2018-01-01

    Background Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients, and is associated to life-threatening complications including increasing risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication. Methods and findings To achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0–3], [4–8] and [9–18] years old. Our results show unexpected results with the development of an atypical obesity with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholosterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to D22), the development of these metabolic deregulations was prevented in adult animals (between 4 and 14 weeks of age

  1. Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia.

    PubMed

    Saint-Laurent, Celine; Garcia, Stephanie; Sarrazy, Vincent; Dumas, Karine; Authier, Florence; Sore, Sophie; Tran, Albert; Gual, Philippe; Gennero, Isabelle; Salles, Jean-Pierre; Gouze, Elvire

    2018-01-01

    Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients, and is associated to life-threatening complications including increasing risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication. To achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0-3], [4-8] and [9-18] years old. Our results show unexpected results with the development of an atypical obesity with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholosterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to D22), the development of these metabolic deregulations was prevented in adult animals (between 4 and 14 weeks of age). The lean-over-fat tissues ratio was

  2. Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection.

    PubMed

    Stittelaar, Koert J; Neyts, Johan; Naesens, Lieve; van Amerongen, Geert; van Lavieren, Rob F; Holý, Antonin; De Clercq, Erik; Niesters, Hubert G M; Fries, Edwin; Maas, Chantal; Mulder, Paul G H; van der Zeijst, Ben A M; Osterhaus, Albert D M E

    2006-02-09

    There is concern that variola virus, the aetiological agent of smallpox, may be used as a biological weapon. For this reason several countries are now stockpiling (vaccinia virus-based) smallpox vaccine. Although the preventive use of smallpox vaccination has been well documented, little is known about its efficacy when used after exposure to the virus. Here we compare the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir (also called HPMPC or Vistide) or with a related acyclic nucleoside phosphonate analogue (HPMPO-DAPy) after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). MPXV causes a disease similar to human smallpox and this animal model can be used to measure differences in the protective efficacies of classical and new-generation candidate smallpox vaccines. We show that initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes. These data show that adequate preparedness for a biological threat involving smallpox should include the possibility of treating exposed individuals with antiviral compounds such as cidofovir or other selective anti-poxvirus drugs.

  3. Early effects of modern electroconvulsive therapy on subjective memory in patients with mania or depression

    PubMed Central

    Bag, Sevda; Canbek, Ozge; Atagun, Ilhan Murat; Kutlar, Tarik Mehmet

    2016-01-01

    Context: Although electroconvulsive therapy (ECT) is considered a very effective tool for the treatment of psychiatric diseases, memory disturbances are among the most important adverse effects. Aims: This study aimed to assess prospectively early subjective memory complaints in depressive and manic patients due to bilateral, brief-pulse ECT, at different stages of the treatment, compare the associations between psychiatric diagnosis, sociodemographic characteristics, and ECT characteristics. Settings and Design: This prospective study was done with patients undergoing ECT between November 2008 and April 2009 at a tertiary care psychiatry hospital of 2000 beds. Materials and Methods: A total of 140 patients, scheduled for ECT with a diagnosis of bipolar disorder (depressive or manic episode) or unipolar depression according to Diagnostic and Statistical Manual of Mental Disorders IV diagnostic criteria, were included in the study and invited to complete the Squire Subjective Memory Questionnaire (SSMQ) before ECT, after the first and third sessions and end of ECT treatment. Statistical Analysis: Mean values were compared with the Kruskal–Wallis test and comparison of the longitudinal data was performed with a nonparametric longitudinal data analysis method, F1_LD_F1 design. Results: SSMQ scores of the patients before ECT were zero. SSMQ scores showed a decrease after the first and third ECT sessions and before discharge, showing a memory disturbance after ECT and were significantly less severe in patients with mania in comparison to those with depression. Conclusions: These findings suggest an increasing degree of subjective memory complaints with bilateral brief-pulse ECT parallel to the increasing number of ECT sessions. PMID:27385854

  4. Prognosis for Mammographically Occult, Early-Stage Breast Cancer Patients Treated With Breast-Conservation Therapy

    SciTech Connect

    Yang, Tzu-I. J.; Yang Qifeng; Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan

    2010-01-15

    Purpose: To compare mammographically occult (MamOcc) and mammographically positive (MamPos) early-stage breast cancer patients treated with breast-conservation therapy (BCT), to analyze differences between the two cohorts. Methods and Materials: Our two cohorts consisted of 214 MamOcc and 2168 MamPos patients treated with BCT. Chart reviews were conducted to assess mammogram reports and method of detection. All clinical-pathologic and outcome parameters were analyzed to detect differences between the two cohorts. Results: Median follow-up was 7 years. There were no differences in final margins, T stage, nodal status, estrogen/progesterone receptor status, or 'triple-negative' status. Significant differences included younger age at diagnosis (pmore » < 0.0001), more positive family history (p = 0.0033), less HER-2+ disease (p = 0.0294), and 1{sup o} histology (p < 0.0001). At 10 years, the differences in overall survival, cause-specific survival, and distant relapse between the two groups did not differ significantly. The MamOcc cohort had more breast relapses (15% vs. 8%; p = 0.0357), but on multivariate analysis this difference was not significant (hazard ratio 1.0, 95% confidence interval 0.993-1.007, p = 0.9296). Breast relapses were mammographically occult in 32% of the MamOcc and 12% of the MamPos cohorts (p = 0.0136). Conclusions: Although our study suggests that there are clinical-pathologic variations for the MamOcc cohort vs. MamPos patients that may ultimately affect management, breast relapse after BCT was not significantly different. Breast recurrences were more often mammographically occult in the MamOcc cohort; consideration should be given to closer follow-up and alternative imaging strategies (ultrasound, breast MRI) for routine posttreatment examination. To our knowledge, this represents the largest series addressing the prognostic significance of MamOcc cancers treated with BCT.« less

  5. Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions?

    PubMed Central

    Tomatsu, Shunji; Montaño, Adriana M.; Oikawa, Hirotaka; Dung, Vu Chi; Hashimoto, Amiko; Oguma, Toshihiro; Takahashi, Tatsuo; Shimada, Tsutomu; Orii, Tadao; Sly, William S.

    2014-01-01

    We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology (1). To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250 units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in liver and spleen, with detectable activity in bone and brain. Second, newborn ERT was conducted after tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th week were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in liver, spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than adult mice treated with ERT; however, hyaline and fibrous cartilage cells in femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mouse. PMID:24953405

  6. TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP)

    PubMed Central

    Lau, Zerlina; Cheung, Pamela; Schneider, William M.; Bozzacco, Leonia; Buehler, Eugen; Takaoka, Akinori; Rice, Charles M.; Felsenfeld, Dan P.; MacDonald, Margaret R.

    2017-01-01

    The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP’s antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP’s ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity. PMID:28060952

  7. TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP).

    PubMed

    Li, Melody M H; Lau, Zerlina; Cheung, Pamela; Aguilar, Eduardo G; Schneider, William M; Bozzacco, Leonia; Molina, Henrik; Buehler, Eugen; Takaoka, Akinori; Rice, Charles M; Felsenfeld, Dan P; MacDonald, Margaret R

    2017-01-01

    The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP's antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP's ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity.

  8. Primary response against cytomegalovirus during antiviral prophylaxis with valganciclovir, in solid organ transplant recipients

    PubMed Central

    La Rosa, Corinna; Limaye, Ajit P.; Krishnan, Aparna; Blumstein, Gideon; Longmate, Jeff; Diamond, Don J.

    2012-01-01

    Antiviral prophylaxis has proved successful for prevention of cytomegalovirus (CMV) disease in solid organ transplant (SOT) patients; though emerging data suggest that antiviral agents interfere with immunity, and may inhibit immune-priming. In this context, we investigated levels and phenotype of primary CMV-specific immune responses that developed during antiviral prophylaxis in a cohort of CMV seronegative recipients (R−) of a SOT from a seropositive donor (D+). We longitudinally monitored CMV viral load, antibodies and levels of the negative immuno-modulator IL-10. PBMC were stimulated with CMV-specific peptide libraries to measure CD137 activation marker on CMV-specific T-cells and levels of PD-1 receptor, which is overexpressed on exhausted T-cells. Unexpectedly, the majority (13/18) of D+R− patients who developed a primary CMV response showed early post-transplant CMV-specific responses, though levels of PD-1 on CMV-specific T-cells remained elevated throughout prophylaxis. A strong inverse association was found between levels of plasma IL-10 and CMV-specific cellular immune responses. Our study suggests that during prophylaxis, subclinical CMV infection might have occurred in the D+R− patients, and primary CMV-specific responses were detected early post-transplant when levels of plasma IL-10 were low. Extended prophylaxis or antiviral treatment did not appear to suppress CMV-specific antibodies or T-cells, which however showed exhaustion phenotypes. PMID:21672050

  9. A review on current status of antiviral siRNA.

    PubMed

    Qureshi, Abid; Tantray, Vaqar Gani; Kirmani, Altaf Rehman; Ahangar, Abdul Ghani

    2018-04-15

    Viral diseases like influenza, AIDS, hepatitis, and Ebola cause severe epidemics worldwide. Along with their resistant strains, new pathogenic viruses continue to be discovered so creating an ongoing need for new antiviral treatments. RNA interference is a cellular gene-silencing phenomenon in which sequence-specific degradation of target mRNA is achieved by means of complementary short interfering RNA (siRNA) molecules. Short interfering RNA technology affords a potential tractable strategy to combat viral pathogenesis because siRNAs are specific, easy to design, and can be directed against multiple strains of a virus by targeting their conserved gene regions. In this review, we briefly summarize the current status of siRNA therapy for representative examples from different virus families. In addition, other aspects like their design, delivery, medical significance, bioinformatics resources, and limitations are also discussed. Copyright © 2018 John Wiley & Sons, Ltd.

  10. Expectations and beliefs in science communication: Learning from three European gene therapy discussions of the early 1990s.

    PubMed

    Meyer, Gitte

    2016-04-01

    There is widespread agreement that the potential of gene therapy was oversold in the early 1990s. This study, however, comparing written material from the British, Danish and German gene therapy discourses of the period finds significant differences: Over-optimism was not equally strong everywhere; gene therapy was not universally hyped. Against that background, attention is directed towards another area of variation in the material: different basic assumptions about science and scientists. Exploring such culturally rooted assumptions and beliefs and their possible significance to science communication practices, it is argued that deep beliefs may constitute drivers of hype that are particularly difficult to deal with. To participants in science communication, the discouragement of hype, viewed as a practical-ethical challenge, can be seen as a learning exercise that includes critical attention to internalised beliefs. © The Author(s) 2014.

  11. Computer-assisted detection (CAD