INTERNAL MEDICINE JOURNAL, Issue 7 2003
G. Ada
Abstract Viral and bacterial vaccines, especially for childhood use, are one of the most successful public health measures of the last two centuries and have a good safety record. However, there are still many diseases that are caused by infectious agents for which vaccines are not available. Our increasing ability to manipulate the immune system offers hope that, in the future, at least some of these infections may be prevented by vaccination. A surprising recent development is the use of vaccine technology to test whether a range of other generally non-communicable diseases can be prevented (or at least controlled) in this way. Investigation of these diseases is still mainly at the experimental level, however the list includes different types of cancers, allergies, drug addiction and neurodegenerative diseases. (Intern Med J 2003; 33: 297,304) [source]

Properties of cell penetrating peptides (CPPs)

IUBMB LIFE, Issue 1 2006
Alexandre Kerkis
Abstract Different approaches have been developed for the introduction of macromolecules, proteins and DNA into target cells. Viral (retroviruses, lentiviruses, etc.) and nonviral (liposomes, bioballistics etc.) vectors as well as lipid particles have been tested as DNA delivery systems. However, all of them share several undesirable effects that are difficult to overcome, such as unwanted immunoresponse and limited cell targeting. The discovery of the cell penetrating peptides (CPPs) showing properties of macromolecules carriers and enhancers of viral vectors, opened new opportunities for the delivery of biologically active cargos, including therapeutically relevant genes into various cells and tissues. This review summarizes recent data about the best characterized CPPs as well as those sharing cell-penetrating and cargo delivery properties despite differing in the primary sequence. The putative mechanisms of CPPs penetration into cells and interaction with intracellular structures such as chromosomes, cytoskeleton and centrioles are addressed. We further discuss recent developments in overcoming the lack of cells specificity, one of the main obstacles for CPPs application in gene therapy. In particular, we review a newly discovered affinity of CPPs to actively proliferating cells. IUBMB Life, 58: 7 - 13, 2006 [source]

Viral interleukin-6 encoded by rhesus macaque rhadinovirus is associated with lymphoproliferative disorder (LPD)

JOURNAL OF MEDICAL PRIMATOLOGY, Issue 2009
B.U. Orzechowska
Abstract Background, Rhesus macaques (RM) co-infected with simian immunodeficiency virus (SIV) and rhesus macaque rhadinovirus (RRV) develop abnormal cellular proliferations characterized as extra-nodal lymphoma and retroperitoneal fibromatosis (RF). RRV encodes a viral interleukin-6 (vIL-6), much like Kaposi's sarcoma-associated herpesvirus, and involvement of the viral cytokine was examined in proliferative lesions. Methods, Formalin fixed tissue from RM co-infected with SIV and RRV were analyzed for RRV genomes by in situ hybridization and RRV vIL-6 expression by immunofluorescence analysis. Results, In situ hybridization analysis indicated that RRV is present in both types of lesions. Immunofluorescence analysis of different lymphomas and RF revealed positive staining for vIL-6. Similarly to KS, RF lesion is positive for vimentin, CD117 (c-kit), and smooth muscle actin (SMA) and contains T cell, B cell and monocytes/macrophage infiltrates. Conclusions, Our data support the idea that vIL-6 may be critical to the development and progression of lymphoproliferative disorder in RRV/SIV-infected RM. [source]

Low- and standard-dose peginterferon alfa-2a for chronic hepatitis C, genotype 2 or 3: efficacy, tolerability, viral kinetics and cytokine response

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2010
Y. ROTMAN
Aliment Pharmacol Ther,31, 1018,1027 Summary Background, Chronic infection with hepatitis C, genotype 2/3, responds better than other genotypes to peginterferon and ribavirin treatment. We hypothesized that a lower dose of peginterferon would be as effective, but less toxic than standard doses. Aim, To test the hypothesis that a lower dose of peginterferon would be as effective as, but less toxic than, standard doses. Methods, A total of 30 patients were treated with low-dose peginterferon alfa-2a (90 ,g/week) and 27 patients with standard doses (180 ,g/week) for 24 weeks in combination with 800 mg/day of ribavirin. Patients who failed treatment were offered 48 weeks of standard-dose treatment. Viral and serum inducible protein 10 (IP-10) levels were measured and early viral kinetic parameters were calculated. Results, Sustained virological response was achieved in 68% of the low-dose and 87% of the standard-dose patients (per protocol, P = 0.79 for non-inferiority). Re-treatment was successful in all patients who tolerated full dose and duration. The standard-dose group had greater first-phase declines of viral levels and faster time to negativity. The second-phase slope was not dose-dependent. IP-10 induction was significantly greater with the standard dose. Although fatigue and general feeling during treatment were worse for standard dose, haematological toxicity and depression did not differ between groups. Conclusion, A lower dose of peginterferon is associated with some symptomatic benefit, but the response is not equivalent to standard dosing. [source]

Cutaneous Pustular Leukemoid Reactions in Trisomy 21

PEDIATRIC DERMATOLOGY, Issue 3 2003
Joanna M. Burch, M.D.
The white blood cell (WBC) counts on the first day of life were markedly elevated, with blasts seen on examination of the peripheral blood smear. The skin eruptions progressed and became pustular. Viral and bacterial cultures were negative. Skin examination revealed pustules on an erythematous base on the cheeks, shoulders, trunk, and proximal extremities. Skin biopsy specimens showed an intraepidermal pustule with an inflammatory infiltrate including neutrophils, eosinophils, and mononuclear cells. The mononuclear cells had atypical, immature-appearing nuclei. In patient 1, these cells were strongly myeloperoxidase positive on immunohistochemistry, indicating myeloid lineage. In patient 2, these cells were CD3-positive T cells. Patient 1 received a 5-day infusion of continuous cytarabine (ara-C) secondary to high WBC counts and symptomatic hyperviscosity. During therapy, the high WBC count and the pustules resolved. The lesions of patient 2 improved with topical mometasone furoate and resolved as her WBC count decreased. Recently, similar cases have been reported. Transient myeloproliferative disorders, or leukemoid reactions, should always be considered when newborns with Down syndrome or trisomy 21 mosaicism develop a pustular eruption. [source]

Viral and atypical bacterial infections in the outpatient pediatric cystic fibrosis clinic,

PEDIATRIC PULMONOLOGY, Issue 12 2006
Hanne Vebert Olesen MD
Abstract Background Respiratory viral and atypical bacterial infections are associated with pulmonary exacerbations and hospitalisations in cystic fibrosis patients. We wanted to study the impact of such infections on children attending the outpatient clinic. Methods Seventy-five children were followed for 12 months at regular clinic visits. Routine sputum/laryngeal aspirations were tested with PCR for 7 respiratory viruses. Antibodies against C. pneumoniae, M. pneumoniae and B. pertussis were measured every 3,4 months. FEV-1, FEF25,75 and specific airway resistance, "viral" symptoms and bacterial culture were recorded. Results Ninety-seven viral and 21 atypical bacterial infections were found. FEV-1 was significantly reduced during viral infection (,12.5%, p=0.048), with the exception of rhinovirus infection. A small change in FEV-1 (,3%) was seen during atypical bacterial infection (p=0.039). Viral and atypical bacterial infections caused no change in type and frequency of bacterial culture. Positive predictive value of "viral symptoms" was low (0.64%). Eight patients received "unnecessary" antibiotics because of viral symptoms. Conclusions Some viral infections and atypical bacterial infections affect FEV-1 acutely. Viral infections did not precipitate bacterial infection or change of colonisation. Clinical symptoms failed to diagnose viral infection accurately. Routine surveillance for virus or atypical bacteria seems not to be justified in this patient category. Pediatr Pulmonol. 2006; 41:1197,1204. © 2006 Wiley-Liss, Inc. [source]

Respiratory Syncytial Viral Infection in an Infant with Unrepaired Anomalous Left Coronary Artery from the Pulmonary Artery

CONGENITAL HEART DISEASE, Issue 4 2007
Karen McClard MD
ABSTRACT Abnormal origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare coronary anomaly in children that requires necessary and urgent repair. We report a child who was hospitalized with respiratory failure due respiratory syncytial viral (RSV) infection and was subsequently diagnosed with ALCAPA. Aggressive treatment for RSV included synagis and nebulized ribavirin prior to surgical repair. After waiting 4 weeks for the RSV infection to resolve, she underwent successful left coronary artery reimplantation on hospital day 27 and has regained normal left ventricular size and function. [source]

Safety and efficacy of vaccines

DERMATOLOGIC THERAPY, Issue 2 2009
Brenda L. Bartlett
ABSTRACT For the past two centuries, vaccines have provided a safe and effective means of preventing a number of infectious diseases. Although the safety of some vaccines has been questioned in recent years, the currently available vaccines are more than a millionfold safer than the diseases they are designed to prevent. Vaccines, however, should always be used in conjunction with other public health interventions. One important intervention is education because the general public can be led to believe that vaccines are unsafe and not needed by misinformation readily available electronically and in print. Not only are some vaccines available via injection but other vaccines are also given orally or intranasally. New vaccines are being studied for topical and intravaginal use. In addition, new systems are being developed for more efficient production of vaccines, especially for influenza. Vaccines are currently available for only a limited number of viral and bacterial diseases. In the future, it is anticipated that safe and effective vaccines will be developed against a number of other viral and bacterial infections as well as fungal and protozoan diseases. [source]

Surveillance of Infectious Disease Occurrences in the Community: An Analysis of Symptom Presentation in the Emergency Department

ACADEMIC EMERGENCY MEDICINE, Issue 7 2003
Joe Suyama MD
Objectives: To determine the effectiveness of a simulated emergency department (ED)-based surveillance system to detect infectious disease (ID) occurrences in the community. Methods: Medical records of patients presenting to an urban ED between January 1, 1999, and December 31, 2000, were retrospectively reviewed for ICD-9 codes related to ID symptomatology. ICD-9 codes, categorized into viral, gastrointestinal, skin, fever, central nervous system (CNS), or pulmonary symptom clusters, were correlated with reportable infectious diseases identified by the local health department (HD). These reportable infectious diseases are designated class A diseases (CADs) by the Ohio Department of Health. Cross-correlation functions (CCFs) tested the temporal relationship between ED symptom presentation and HD identification of CADs. The 95% confidence interval for lack of trend correlation was 0.0 ± 0.074; thus CCFs > 0.074 were considered significant for trend correlation. Further cross-correlation analysis was performed after chronic and non-community-acquirable infectious diseases were removed from the HD database as a model for bioterrorism surveillance. Results: Fifteen thousand five hundred sixty-nine ED patients and 6,489 HD patients were identified. Six thousand two hundred eight occurrences of true CADs were identified. Only 87 (1.33%) HD cases were processed on weekends. During the study period, increased ED symptom presentation preceded increased HD identification of respective CADs by 24 hours for all symptom clusters combined (CCF = 0.112), gastrointestinal symptoms (CCF = 0.084), pulmonary symptoms (CCF = 0.110), and CNS symptoms (CCF = 0.125). The bioterrorism surveillance model revealed increased ED symptom presentation continued to precede increased HD identification of the respective CADs by 24 hours for all symptom clusters combined (CCF = 0.080), pulmonary symptoms (CCF = 0.100), and CNS symptoms (CCF = 0.120). Conclusions: Surveillance of ED symptom presentation has the potential to identify clinically important ID occurrences in the community 24 hours prior to HD identification. Lack of weekend HD data collection suggests that the ED is a more appropriate setting for real-time ID surveillance. [source]

Gene therapy in epilepsy

EPILEPSIA, Issue 1 2009
Véronique Riban
Summary Results from animal models suggest gene therapy is a promising new approach for the treatment of epilepsy. Several candidate genes such as neuropeptide Y and galanin have been demonstrated in preclinical studies to have a positive effect on seizure activity. For a successful gene therapy-based treatment, efficient delivery of a transgene to target neurons is also essential. To this end, advances have been made in the areas of cell transplantation and in the development of recombinant viral vectors for gene delivery. Recombinant adeno-associated viral (rAAV) vectors in particular show promise for gene therapy of neurological disorders due to their neuronal tropism, lack of toxicity, and stable persistence in neurons, which results in robust, long-term expression of the transgene. rAAV vectors have been recently used in phase I clinical trials of Parkinson's disease with an excellent safety profile. Prior to commencement of phase I trials for gene therapy of epilepsy, further preclinical studies are ongoing including evaluation of the therapeutic benefit in chronic models of epileptogenesis, as well as assessment of safety in toxicological studies. [source]

Functional plasticity and robustness are essential characteristics of biological systems: Lessons learned from KLRG1-deficient mice

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010
Stipan Jonjic
Abstract Killer cell lectin-like receptor G1 (KLRG1) receptor is considered to be a marker of terminally differentiated NK and T cells and is strongly induced by viral and other infections. KLRG1 is a C-type lectin-like inhibitory receptor, which interacts with members of the cadherin family of molecules leading to the inhibition of T- and NK-cell function. A study in this issue of the European Journal of Immunology addresses the role of KLRG1 in the maturation and differentiation of NK and T cells in vivo. Using KLRG1-deficient mice generated by homologous recombination, the study reveals that KLRG1 is dispensable for NK- and CD8+ T-cell differentiation and function in vivo. This interesting finding is discussed in this Commentary in light of the plasticity and robustness of immune response mechanisms. [source]

Effector T-cell differentiation during viral and bacterial infections: Role of direct IL-12 signals for cell fate decision of CD8+ T cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2009
Selina J. Keppler
Abstract To study the role of IL-12 as a third signal for T-cell activation and differentiation in vivo, direct IL-12 signaling to CD8+ T cells was analyzed in bacterial and viral infections using the P14 T-cell adoptive transfer model with CD8+ T cells that lack the IL-12 receptor. Results indicate that CD8+ T cells deficient in IL-12 signaling were impaired in clonal expansion after Listeria monocytogenes infection but not after infection with lymphocytic choriomeningitis virus, vaccinia virus or vesicular stomatitis virus. Although limited in clonal expansion after Listeria infection, CD8+ T cells deficient in IL-12 signaling exhibited normal degranulation activity, cytolytic functions, and secretion of IFN-, and TNF-,. However, CD8+ T cells lacking IL-12 signaling failed to up-regulate KLRG1 and to down-regulate CD127 in the context of Listeria but not viral infections. Thus, direct IL-12 signaling to CD8+ T cells determines the cell fate decision between short-lived effector cells and memory precursor effector cells, which is dependent on pathogen-induced local cytokine milieu. [source]

Cross-priming of CD8+ T,cells by viral and tumor antigens is a robust phenomenon

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2004
Weisan Chen
Abstract "Cross-priming" refers to the activation of naive CD8+ T,cells by antigen-presenting cells that have acquired nominal antigens from another cell. The biological relevance of cross-priming of CD8+ T,cells has recently been challenged (Zinkernagel, R. M., Eur. J. Immunol. 2002. 32: 2385,2392), on the basis that responses are weak or poorly quantitated, and the determinants recognized are undefined. Here we show that cross-priming is a robust process that elicits vigorous primary responses to multiple peptides in two well-defined systems. Our findings support the relevance of cross-priming in CD8+ T,cell responses to viruses and tumor cells, and demonstrate that cross-priming elicits CD8+ T,cells to determinants generated by the endogenous processing pathway. [source]

HEPATITIS C AND ADDICTION: Retention rate and side effects in a prospective trial on hepatitis C treatment with pegylated interferon alpha-2a and ribavirin in opioid-dependent patients

ADDICTION BIOLOGY, Issue 2 2009
Nina Ebner
ABSTRACT Hepatitis C viral (HCV) infection is present in 30 to 98% of intravenous drug users. Intravenous substance abuse represents the main route of HCV transmission in industrialized countries. A multi-centre, randomized, controlled, prospective study assessed sustained virological response (SVR), adverse events such as depressive episodes and retention rate of HCV treatment in opioid-dependent patients. Stabilized, opioid-dependent patients with chronic HCV infection (genotype 2 or 3) received pegylated interferon alpha-2a in combination with ribavirin 800 mg/day (Group A) or 400 mg/day (Group B). Participants were randomized, blocked and stratified by genotype and viral load. A standardized psychiatric assessment, Beck Depression Inventory (BDI) and Van Zerssen's list of complaints were administered at each study visit. In 31 months, 300 opioid-dependent patients were screened; 190 (63.3%) were hepatitis C antibody positive. According to study protocol, out of 75 ,potential-to-treat' patients with genotype 2 or 3, 17 stable patients (22.6%) were included in the study. All participants completed the study. Significant haemoglobin decreases occurred in both Groups A (P = 0.001) and B (P = 0.011). All the patients had an end-of-treatment (week 24) HCV RNA negativity. Fifteen (88.2%) achieved SVR at week 48. Overall, 52.9% developed depressive symptoms during treatment. Because of the prompt initiation of antidepressant medication at first appearance of depressive symptoms, no severe depressive episodes occurred. Our data show a high retention rate and reliability, and good viral response for both treatments. Hepatitis C treatment in stable opioid-dependent patients was efficacious, suggesting that addiction clinics can offer antiviral therapy in combination with agonistic treatment as part of multi-disciplinary treatment. [source]

Crystal structures of Nipah and Hendra virus fusion core proteins

FEBS JOURNAL, Issue 19 2006
Zhiyong Lou
The Nipah and Hendra viruses are highly pathogenic paramyxoviruses that recently emerged from flying foxes to cause serious disease outbreaks in humans and livestock in Australia, Malaysia, Singapore and Bangladesh. Their unique genetic constitution, high virulence and wide host range set them apart from other paramyxoviruses. These characteristics have led to their classification into the new genus Henpavirus within the family Paramyxoviridae and to their designation as Biosafety Level 4 pathogens. The fusion protein, an enveloped glycoprotein essential for viral entry, belongs to the family of class I fusion proteins and is characterized by the presence of two heptad repeat (HR) regions, HR1 and HR2. These two regions associate to form a fusion-active hairpin conformation that juxtaposes the viral and cellular membranes to facilitate membrane fusion and enable subsequent viral entry. The Hendra and Nipah virus fusion core proteins were crystallized and their structures determined to 2.2 Å resolution. The Nipah and Hendra fusion core structures are six-helix bundles with three HR2 helices packed against the hydrophobic grooves on the surface of a central coiled coil formed by three parallel HR1 helices in an oblique antiparallel manner. Because of the high level of conservation in core regions, it is proposed that the Nipah and Hendra virus fusion cores can provide a model for membrane fusion in all paramyxoviruses. The relatively deep grooves on the surface of the central coiled coil represent a good target site for drug discovery strategies aimed at inhibiting viral entry by blocking hairpin formation. [source]

Initiation of JC virus DNA replication in vitro by human and mouse DNA polymerase ,-primase

FEBS JOURNAL, Issue 9 2003
Richard W. P. Smith
Host species specificity of the polyomaviruses simian virus 40 (SV40) and mouse polyomavirus (PyV) has been shown to be determined by the host DNA polymerase ,-primase complex involved in the initiation of both viral and host DNA replication. Here we demonstrate that DNA replication of the related human pathogenic polyomavirus JC virus (JCV) can be supported in vitro by DNA polymerase ,-primase of either human or murine origin indicating that the mechanism of its strict species specificity differs from that of SV40 and PyV. Our results indicate that this may be due to differences in the interaction of JCV and SV40 large T antigens with the DNA replication initiation complex. [source]

Evidence that viral abundance across oceans and lakes is driven by different biological factors

FRESHWATER BIOLOGY, Issue 6 2008
JESSICA L. CLASEN
Summary 1. Samples from 16 lakes in central (n = 145) and western (n = 12) North America, the coastal northeast Pacific (n = 302) and the western Canadian Arctic Oceans (n = 142) were collected and analysed for viral, bacterial and cyanobacterial abundances and chlorophyll- a concentration. 2. Viral abundance was significantly different among the environments. It was highest in the coastal Pacific Ocean and lowest in the coastal Arctic Ocean. The abundances of bacteria and cyanobacteria as well as chlorophyll- a concentrations also differed significantly among the environments, with both bacterial abundance and chlorophyll- a concentration highest in lakes. As a consequence, the association of these variables with viral abundance varied among the environments. 3. Discriminant analyses with the abundance data indicated that the marine and freshwater environments were predictably different from each other. Multiple-regression analysis included bacterial and cyanobacterial abundances, and chlorophyll- a concentration as significant variables in explaining viral abundance in lakes. In regression models for the coastal Pacific Ocean, bacterial and cyanobacterial abundances were significant variables, and for the coastal Arctic Ocean viral abundance was predicted by bacterial abundance and chlorophyll- a concentration. 4. The relationship of viral and bacterial abundance differed between the investigated freshwater and marine environments, probably because of differences in viral production and loss rates. However, freshwaters had fewer viruses compared to bacteria, despite previously documented higher burst sizes and frequencies of infected cells, suggesting that loss rates may be more important in lakes. 5. Together, these findings suggest that there are different drivers of viral abundance in different aquatic environments, including lakes and oceans. [source]

PEI,PEG,Chitosan-Copolymer-Coated Iron Oxide Nanoparticles for Safe Gene Delivery: Synthesis, Complexation, and Transfection

ADVANCED FUNCTIONAL MATERIALS, Issue 14 2009
Forrest M. Kievit
Abstract Gene therapy offers the potential of mediating disease through modification of specific cellular functions of target cells. However, effective transport of nucleic acids to target cells with minimal side effects remains a challenge despite the use of unique viral and non-viral delivery approaches. Here, a non-viral nanoparticle gene carrier that demonstrates effective gene delivery and transfection both in vitro and in vivo is presented. The nanoparticle system (NP,CP,PEI) is made of a superparamagnetic iron oxide nanoparticle (NP), which enables magnetic resonance imaging, coated with a novel copolymer (CP,PEI) comprised of short chain polyethylenimine (PEI) and poly(ethylene glycol) (PEG) grafted to the natural polysaccharide, chitosan (CP), which allows efficient loading and protection of the nucleic acids. The function of each component material in this nanoparticle system is illustrated by comparative studies of three nanoparticle systems of different surface chemistries, through material property characterization, DNA loading and transfection analyses, and toxicity assessment. Significantly, NP,CP,PEI demonstrates an innocuous toxic profile and a high level of expression of the delivered plasmid DNA in a C6 xenograft mouse model, making it a potential candidate for safe in vivo delivery of DNA for gene therapy. [source]

Putting flesh and polish on autoimmune hepatitis and moving the disease of exclusion to inclusion,

HEPATOLOGY, Issue 4 2010
Albert J. Czaja
Autoimmune hepatitis emerged during an era when concepts of neonatal immune tolerance, clonal selection of lymphocytes, and "forbidden clones" of activated immune cells were forming. The diagnosis had to be deduced from circumstantial evidence and by exclusion of other conditions. The goals of this review are to demonstrate how a clinician nonscientist can contribute to the maturation of autoimmune hepatitis and to illustrate the principles of clinical investigation that can be applied broadly to other projects. Autoimmune hepatitis initially had to be distinguished from other diseases, and improvements in the tests for viral and immune markers were instrumental in this regard. Diversification of the clinical phenotype to accommodate acute severe, asymptomatic, elderly, and variant forms enhanced the pertinence of the disease, and the formation of the International Autoimmune Hepatitis Group standardized the diagnosis, interconnected investigators, and promoted global acceptance of the condition. Subsequent studies refined current corticosteroid-based therapies, identified prognostic markers, assessed genetic predispositions, explored new pharmacological agents, and forecast the emergence of cellular and molecular interventions. Good fortune, stimulating mentors, career dedication, practical goal selection, protocol compliance, compulsive record keeping, personal resilience, and strong collaborations were the bases for progress. Autoimmune hepatitis exemplifies an evolutionary process in the science of autoimmunity and the people committed to its study. Lessons derived from this experience can be far-reaching. (HEPATOLOGY 2010;52:1177-1184) [source]

Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in patients with chronic hepatitis C, using viral and host factors: Some concerns,

HEPATOLOGY, Issue 6 2009
Chia-Yen Dai
No abstract is available for this article. [source]

Incubation phase of acute hepatitis B in man: Dynamic of cellular immune mechanisms

HEPATOLOGY, Issue 5 2000
George J.M. Webster
After hepatitis B virus (HBV) infection, liver injury and viral control have been thought to result from lysis of infected hepatocytes by virus-specific cytotoxic T cells. Patients are usually studied only after developing significant liver injury, and so the viral and immune events during the incubation phase of disease have not been defined. During a single-source outbreak of HBV infection, we identified patients before the onset of symptomatic hepatitis. The dynamics of HBV replication, liver injury, and HBV-specific CD8+ and CD4+ cell responses were investigated from incubation to recovery. Although a rise in alanine transaminase (ALT) levels was present at the time of the initial fall in HBV-DNA levels, maximal reduction in virus level occurred before significant liver injury. Direct ex vivo quantification of HBV-specific CD4+ and CD8+ cells, by using human leukocyte antigen (HLA) class I tetramers and intracellular cytokine staining, showed that adaptive immune mechanisms are present during the incubation phase, at least 4 weeks before symptoms. The results suggest that the pattern of reduction in HBV replication is not directly proportional to tissue injury during acute hepatitis B in humans. Furthermore, because virus-specific immune responses and significant reductions in viral replication are seen during the incubation phase, it is likely that the immune events central to viral control occur before symptomatic disease. [source]

The importance of steatosis in chronic hepatitis C infection and its management: A review

HEPATOLOGY RESEARCH, Issue 3 2010
Timothy J. S. Cross
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease with approximately 180 million people infected worldwide. Hepatic steatosis is a frequent histological finding in chronic hepatitis C (CHC) infection and is 2- to 3-fold more common than would be expected by chance alone. A high body mass index with excess visceral fat distribution is associated with steatosis in patients infected with HCV genotype 1 but not genotype 3, re-enforcing the concept that in patients with CHC, some have "metabolic steatosis", predominantly HCV genotype 1, and others "viral steatosis", mainly HCV genotype 3. Accumulating evidence suggests that steatosis may contribute to progression of fibrosis in CHC. Hepatic insulin resistance appears to play a role through the pro-fibrogenic effects of compensatory hyperinsulinemia. The aim of this review was to assess the effect host and viral factors play in steatosis development in patients with CHC infection and its possible relationship with hepatocellular carcinoma. The review examines the mechanisms by which CHC infection causes hepatic steatosis, the impact hepatic steatosis has on the natural history of the disease and finally, explores if treatments leading to a reduction in the amount of steatosis might lead to improved treatment outcomes. The basic medical science of steatosis in CHC will be discussed including proposed models of steatogenesis and the influence of viral and metabolic factors at the molecular level and how these might impact on current and future therapies. [source]

Progress toward liver-based gene therapy

HEPATOLOGY RESEARCH, Issue 4 2009
Takeshi Suda
The liver is involved in the synthesis of serum proteins, regulation of metabolism and maintenance of homeostasis and provides a variety of opportunities for gene therapy. The enriched vasculature and blood circulation, fenestrated endothelium, abundant receptors on the plasma membranes of the liver cells, and effective transcription and translation machineries in the hepatocytes are some unique features that have been explored for delivery, and functional analysis, of genetic sequences in the liver. Both viral and non-viral methods have been developed for effective gene delivery and liver-based gene therapy. This review describes the fundamentals of gene delivery, and the preclinical and clinical progress that has been made toward gene therapy using the liver as a target. [source]

Antiviral activity of low-dose alovudine in antiretroviral-experienced patients: results from a 4-week randomized, double-blind, placebo-controlled dose-ranging trial,

HIV MEDICINE, Issue 3 2007
J Ghosn
Background Alovudine inhibits replication of highly nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV strains in vitro. However, dose-dependent safety concerns resulted in its initial development being halted. Recently, a 4-week course of alovudine 7.5 mg/day added to a stavudine-free failing regimen yielded a significant decrease in viral load by ,1.88 log10 HIV-1 RNA copies/mL. The magnitude of the reduction in viral load suggested that lower doses might still be effective while offering adequate safety during long-term use. Objective To determine whether lower dosages of alovudine still provide significant antiviral activity in patients with broad NRTI resistance. Methods A randomized, double-blind, placebo-controlled trial investigating three doses of alovudine (0.5, 1 and 2 mg) or placebo added for 4 weeks to a failing regimen in patients with evidence of NRTI-resistant HIV strains [,2 thymidine-associated mutations (TAMs)]. The primary endpoint was the mean viral load reduction between baseline and week 4. Results Seventy-two patients were enrolled in the study: 21, 13, 18 and 20 in the placebo and 0.5, 1 and 2 mg arms, respectively. Baseline median CD4 count and viral load were 298 cells/,L (range 44,692 cells/,L) and 3.9 log10 copies/mL (range 2.5,5.2 log10 copies/mL), respectively. Baseline viral isolates harboured a median of four TAMs. Alovudine was added to a median four-drug failing regimen. At week 4, compared with placebo, mean viral load changes were ,0.42 log10 [95% confidence interval (CI) ,0.67 to ,0.18] and ,0.30 log10 (,0.55 to ,0.06) in the 2 and 1 mg arms, respectively. There was no significant change in CD4 cell count. Alovudine was well tolerated. Conclusion: A 4-week course of alovudine 2 mg/day provided a modest but significant viral load reduction in patients harbouring viruses with a median of four TAMs. [source]

Influenza virus assays based on virus-inducible reporter cell lines

INFLUENZA AND OTHER RESPIRATORY VIRUSES, Issue 5 2009
Yunsheng Li
Background, Virus-inducible reporter genes have been used as the basis of virus detection and quantitation assays for a number of viruses. A strategy for influenza A virus-induction of a reporter gene was recently described. In this report, we describe the extension of this strategy to influenza B virus, the generation of stable cell lines with influenza A and B virus-inducible reporter genes, and the use of these cells in various clinically relevant viral assays. Each of the cell lines described herein constitutively express an RNA transcript that contains a reporter gene coding region flanked by viral 5,- and 3,-untranslated regions (UTR) and therefore mimics an influenza virus genomic segment. Upon infection of the cells with influenza virus the virus-inducible reporter gene segment (VIRGS) is replicated and transcribed by the viral polymerase complex resulting in reporter gene expression. Findings, Reporter gene induction occurs after infection with a number of laboratory strains and clinical isolates of influenza virus including several H5N1 strains. The induction is dose-dependent and highly specific for influenza A or influenza B viruses. Conclusions, These cell lines provide the basis of simple, rapid, and objective assays that involve virus quantitation such as determination of viral titer, assessment of antiviral susceptibility, and determination of antibody neutralization titer. These cell lines could be very useful for influenza virus researchers and vaccine manufacturers. [source]

Improving methods of assessing natural killer cell cytotoxicity

INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH, Issue 1 2006
Sandra E. Sephton
Abstract Natural killer (NK) cells are a class of lymphocytes important in immune resistance to viral and other serious diseases. The cytotoxic function, or ,killing activity' of NK cells has become important in studies of the effects of stress and other psychosocial factors on physical health. Unfortunately, research on NK cell function has been plagued by discrepancies in the methods of interpreting NK cytotoxicity data. We briefly review some of the variations in measuring NK cell activity and present a new model for interpreting these results, introducing maximal target cell lysis (A) and the slope of the cytolytic curve (k) as parameters that attempt to make full use of the information and the statistical power in NK cell cytotoxicity data. Examples of these interpretation methods are presented using NK cytotoxicity data from a group of metastatic breast cancer patients. This approach will be useful in applications of NK cell measurement in psychoneuroimmunology research. Copyright © 2006 John Wiley & Sons, Ltd. [source]

RNase L: Its biological roles and regulation

IUBMB LIFE, Issue 9 2006
Shu-Ling Liang
Abstract 2'-5'oligoadenylate-dependent ribonuclease L (RNase L) is one of the key enzymes involved in the function of interferons (IFNs), a family of cytokines participating in innate immunity against viruses and other microbial pathogens. Upon binding with its activator, 5'-phosphorylated, 2'-5' linked oligoadenylates (2-5A), RNase L degrades single-stranded viral and cellular RNAs and thus plays an important role in the antiviral and antiproliferative functions of IFNs. In recent years, evidence has revealed that RNase L displays a broad range of biological roles which are summarized in this review. iubmb Life, 58: 508-514, 2006 [source]

The Role of DNA Recombination in Herpes Simplex Virus DNA Replication

IUBMB LIFE, Issue 8 2003
Dianna Wilkinson
Abstract In many organisms the processes of DNA replication and recombination are closely linked. For instance, in bacterial and eukaryotic systems, replication forks can become stalled or damaged, in many cases leading to the formation of double stranded breaks. Replication restart is an essential mechanism in which the recombination and repair machinery can be used to continue replication after such a catastrophic event. DNA viruses of bacteria such as lambda and T4 also rely heavily on DNA recombination to replicate their genomes and both viruses encode specialized gene products which are required for recombination-dependent replication. In this review, we examine the linkage between replication and recombination in the eukaryotic pathogen, Herpes Simplex Virus Type 1 (HSV-1). The evidence that recombination plays an intrinsic role in HSV-1 DNA replication and the infection process will be reviewed. We have recently demonstrated that HSV-1 encodes two proteins which may be analogous to the lambda phage recombination system, Red ,and ,. The HSV-1 alkaline nuclease, a 5' to 3' exonuclease, and ICP8, a single stranded DNA binding protein, can carry out strand annealing reactions similar to those carried out by the lambda Red system. In addition, evidence suggesting that host recombination proteins may also be important for HSV-1 replication will be reviewed. In summary, it is likely that HSV-1 infection will require both viral and cellular proteins which participate in various pathways of recombination and that recombination-dependent replication is essential for the efficient replication of viral genomes. IUBMB Life, 55: 451-458, 2003 [source]

Emerging targets and novel strategies in the treatment of AIDS-related Kaposi's sarcoma: Bidirectional translational science

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006
Bruce J. Dezube
Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research,not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed. J. Cell. Physiol. 209: 659,662, 2006. © 2006 Wiley-Liss, Inc. [source]

Neutropenia, thrombocytopenia and hepatic injury associated with dexketoprofen trometamol therapy in a previously healthy 35-year-old woman

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2008
S. Zabala MD
Summary This case report describes a previously healthy 35-year-old woman, with an episode of fever, neutropenia, thrombocytopenia and elevation of biochemical markers of liver injury, 10 days after beginning drug therapy with dexketoprofen trometamol. Infectious and autoimmune causes of neutropenia, and viral or autoimmune hepatitis were excluded. The resolution following withdrawal of dexketoprofen trometamol confirms the possibility of an adverse drug reaction. [source]