Hepatitis Ebook

Alternative Hepatitis C Treatments

The therapeutic goals of Natural treatment for Hepatitis C are as follows: Decrease iral load Normalize liver enzyme levels. Enhance/regulate immune system function. Strengthen and promote healthy liver function. Protect the liver, prevent further damage. Virological response; i.e. viral clearance, viral reduction or elimination of the virus. Starve the virus by limiting levels of iron. Optimizing cellular levels of glutathione in the body, making detoxification of the liver possible and enhancing the immune system. Stimulate regeneration of the damaged liver cells. Use of antioxidants to combat the effects of free-radicals generated by the virus. Reduce inflammation. Slow viral replication. Replace all of the inflammation-damaged liver cells. Regulate immune function/prevent auto-immune problems. Cancer preventative measures. Reverse fibrosis to prevent and improve cirrhosis

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Hepatitis Introduction

Hepatitis is the inflammation of the liver usually caused by a virus. Four viruses that may cause it are hepatitis A (HAV), hepatitis B (HBV), hepatitis D (HDV) and hepatitis non-A, non-B (NANB). Most common of the types found in children is hepatitis A which is transmitted by the fecal-oral route. The incidence in children is increased in those living in crowded housing. The disorder is usually self-limiting with resolution within 2 to 3 months or may develop into chronic hepatitis. Symptomology varies with severity of the disease.

Progress On New Hepatitis C Virus Targets Ns2 And Ns5a

Hepatitis C virus (HCV) is a major global health problem, affecting about 170 million people worldwide. Chronic infection can lead to cirrhosis and liver cancer. The replication machine of HCV is a multi-subunit membrane associated complex, consisting of nonstructural proteins (NS2-5B), which replicate the viral RNA genome. The structures of NS5A and NS2 were recently determined. NS5A is an essential replicase component that also modulates numerous cellular processes ranging from innate immunity to cell growth and survival. The structure reveals a novel protein fold, a new zinc coordination motif, a disulfide bond and a dimer interface. Analysis of molecular surfaces suggests the location of the membrane interaction surface of NS5A, as well as hypothetical protein and RNA binding sites. NS2 is one of two virally encoded proteases that are required for processing the viral polyprotein into the mature nonstructural proteins. NS2 is a dimeric cysteine protease with two...

Treatment of Chronic Hepatitis B

Prior to the introduction of specific antiviral therapeutics, persistent HBV infection was treated with interferon, with mixed success. In some studies, up to one-third of treated individuals cleared the virus, but the treatment was rather less successful in certain populations, particularly individuals from the Far East. Interferon seems to work by modulating the immune response of the host, rather than a direct antiviral effect, and was found to be most successful in individuals who had evidence of hepatitis or, in other words, already were mounting a cellular immune response to the virus. Figure 5 Expression of the HBV core ORF. The pregenomic RNA is translated from the second initiation codon in the ORF to yield HBcAg. The precore RNA is translated from the upstream initiation codon to p25, which is processed to HBeAg. The arrow indicates the position of the most common precore mutation, changing a tryptophan to a termination codon. Reproduced from Harrison TJ (2006) Hepatitis B...

The Amplicor HCV Monitor 20 and Cobas Amplicor HCV Monitor 20 Test Roche Diagnostic Systems

Based on reverse transcription polymerase chain reaction (RT-PCR), the Amplicor HCV Monitor test (Roche Diagnostic Systems) was developed. 5 Recently, an improved version 2.0 was introduced, which achieved an equivalent quantitation of each genotype over the quantitative range (5 x 102 to 5 x 105 copies of RNA mL). 6,7 HCV RNA is extracted from plasma by chaotropic salt and is then precipitated by isopropanol. Both RT and PCR of RNA are accomplished in one tube using the recombinant thermostable DNA polymerase (rTth), which offers both reverse transcriptase activity, forming a cDNA from the RNA target sequence of the 5' UTR, and polymerase activity for amplification of the cDNA under appropriate conditions. An internal quantification standard shows the same primer-binding sites as the target but with a changed internal sequence, which allows binding to special detection probes. This allows quantification after a series of dilutions at the end of the assay. To meet the needs of routine...

The Hepatitis B Vaccines

The hepatitis B vaccines contain HBsAg and are given via an intramuscular injection to stimulate a protective anti-HBs response. The first-generation (so-called 'plasma derived') vaccine was produced by purifying HBsAg from donated blood. Despite some worries that blood-borne viruses (particularly human immunodeficiency virus (HIV)) potentially might contaminate particular batches, this method of vaccine production is safe provided that manufacturing protocols, including steps that inactivate potential infec-tivity, are adhered to strictly. Even today, plasma-derived vaccines constitute the majority of doses given worldwide. Currently, most doses of hepatitis B vaccine given in the West are produced by expression of HBsAg in yeast (Saccharomyces cerevisiae), and several vaccines based on expression in mammalian cells also have been licensed. Most countries worldwide have now introduced universal immunization of infants. Although the vaccine may be incorporated into the Expanded...

HCV Replication Cycle

HCV infection starts by binding the envelope glycoprotein E1 E2 complex on the surface of the virus particle to its cognate receptor(s) presumably leading to clathrin-mediated endocytosis and a subsequent fusion step from within an acidic endosomal compartment (Figure 3). Cellular factors implicated in virus binding and entry are glycosaminoglycans, scavenger receptor class B type 1 (SR-B1), CD81, and low-density lipoprotein (LDL) receptor. However, for most of these factors, the precise role is not well understood and one or several additional factors may be required for productive entry. Upon release of the RNA genome, the polyprotein is expressed by IRES-dependent translation occurring at the rough endoplasmic reticulum (rER) where host cell signal peptidases, signal peptide peptidases, and viral proteases catalyze polyprotein cleavage.

Differentially Expressed Genes Associated With Hepatitis B Virus HBx and MHBs Protein Function in Hepatocellular

HBx and MHBs' products from hepatitis B virus-DNA (HBV-DNA), which become transcriptional transactivators of cellular and viral genes, are known to play causative roles in the development of hepatocellular carcinoma (HCC). However, the biomolecular mechanism(s) for their roles in hepatocarcinogenesis in vivo remain poorly understood. To identify authentic cellular genes involved in HBx and MHBsl-transactivated carcinogenesis, we used mRNA differential display polymerase chain reaction (DD-PCR). We examined HBx and MHBs-positive or -negative HCC, which had chromosomally integrated HBV DNA, vs nontumor tissues, respectively, and differentially expressed genes in either type of HCC were identified and compared with each other. Using 240 different combinations of three one-base anchored oligo-dT primers and 80 arbitrary 13mers, 16 genes were differentially expressed in the HBx and MHBs-positive HCC including Ro RNA hY1, glutamine synthetase, factor H homologue 3' end, voltage-dependent...

Hepatitis B

Hepatitis B, or serum hepatitis, is spread mainly through contaminated blood, often from unsterilized needles shared by drug users or used for tattoos or ear or body piercing. The virus can also be transmitted sexually. Over 100,000 people are infected yearly in the United States, but this number is decreasing due to the recent introduction of a vaccine. In addition to the initial disease, which is more severe than hepatitis A (more liver damage and fatality rate of 10 ), those infected are at higher risk of liver cancer.

Hcv Ns5a

NS5A is an active component of the HCV RNA replicase, a pivotal regulator of replication, and a modulator of numerous cellular processes spanning from innate immunity to apoptosis and disregulated cell growth.29'41 It exists as a serine phosphoprotein present in hypo- (56 kDa) and hyper-phosphorylated (58 kDa) forms. An amphipathic a-helix at its N terminus promotes association with cellular membranes.4'8'32 Following this helix, NS5A is organized into three domains (Fig. 2A)40 The N-terminal domain (domain I) coordinates a single zinc atom per protein molecule.40 Mutations disrupting either the membrane anchor8,32 or zinc binding40 are lethal for HCV RNA replication. NS5A interacts with other viral components of the replicase7 and has been shown to modulate NS5B polymerase activity in vitro.37'38 NS5A domain II and the region connecting domain I and II are hotspots for adaptive mutations that can enhance replication in cell culture by more that 10,000-fold.2'26 Such highly adaptive...

Hepatitis Viruses

Hepatitis A virus or hepatitis delta and epsilon viruses have been uncommon sources of hepatitis in transplant patients. In contrast, infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) have been frequent. Transplant patients may be more susceptible to the complications of HBV and HCV infection, but the uncertainty regarding epidemiology and pathogenesis of these infections complicates decisions regarding the suitability of patients with hepatitis for transplant. There have been many impediments to an understanding of the consequence of hepatitis. Until the recent development of the anti-HCV assay, the course of patients with HCV infection could not be distinguished from the course of patients with other hepatic abnormalities. Even though patients with HCV can now be identified, the current assay is insensitive. Meanwhile, assays for HBV infection, long considered sensitive and specific, do not adequately detail the potential for HBV reactivation and infectivity. Thus,...

HCVHost Interaction

Several cellular proteins appear to contribute to HCV replication. For example, the ubiquitously expressed human vesicle-associated membrane protein-associated protein A (VAP-A) and its isoform VAP-B were identified as interaction partners of NS5A and NS5B. NS5A hyperphosphorylation seems to disrupt the VAP-A association and thereby negatively regulates HCV RNA replication. It is thought that VAP-A directs HCV nonstructural proteins to cholesterol-rich, detergent-resistant membranes, which are the presumed sites of HCV RNA replication. Another host cell factor interacting with NS5A is FBL-2 belonging to the family of proteins that contain an F box and multiple leucine-rich repeats. FBL-2 is modified by geranylgeranylation which is important for NS5A interaction. FBL-2 appears to be required for HCV RNA replication. Likewise, Cyclophilin B (CyPB), a cellular protein interacting with the NS5B RdRp, seems to contribute to replication of genotype 1 isolates by promoting RNA-binding...

Hepatitis

Of hepatitis are self-limiting and resolve without complications. Hospitalization is required only when symptoms are severe, persistent, or debilitating. Approximately 20 of acute hepatitis B and 50 of hepatitis C cases progress to a chronic state. In Americans, 5 to 10 of patients with hepatitis have hepatitis B virus (HBV) infections. In third world countries, the rates are much higher. The most serious complication of hepatitis is fulminant hepatitis, which occurs in approximately 1 of all patients and leads to liver failure and hepatic encephalopathy and, in some, to death within 2 weeks of onset. Other complications include a syndrome that resembles serum sickness (muscle and joint pain, rash, angioedema), as well as cirrhosis, pancreatitis, myocarditis, aplastic anemia, or peripheral neuropathy.

Hepatitis D Virus

HDV merits a brief mention because of its particular association with HBV. As noted above, a novel antigen, termed delta, was discovered in patients with hepatitis B and this turned out to be the nucleocapsid protein of HDV. The HDV genome is a single-stranded circle of RNA that resembles the viroids and virusoids of plants it is believed to be replicated by the host RNA polymerase II, with cleavage and rejoining of the circle mediated by a ribozyme activity. Unlike the viroids and virusoids, HDV was first discovered in Italy and is found in the Mediterranean area, reportedly with a declining prevalence, and also in the Far East and South America. The virus may be acquired as a coinfection with HBV or by super-infection of someone already HBsAg-positive. In both cases, disease may be more severe than with HBV alone, and chronic delta hepatitis may progress to cirrhosis more frequently, and more rapidly, than chronic hepatitis B. The hepatitis B vaccine also protects against...

Hcv Rna Quantitation

Quantitation of HCV RNA by bDNA technology is possible with the commercial VERSANT HCV RNA 3.0 assay. The performance characteristics of this test were established in our laboratory during the so-called ''beta trials'' before licensing and are given in Table 1. 4 Our findings were essentially confirmed by other studies, 11,12 and showed that the assay, from an analytical point of view, can be used as a routine tool for HCV RNA quantitation in clinical laboratory settings. Table 1 Analytical performance characteristics of VERSANT HCV RNA 3.0 assay Table 1 Analytical performance characteristics of VERSANT HCV RNA 3.0 assay

Prevention and Therapy

In the veterinary practice, dog vaccination schedules all over the world invariably include a live or killed CAdV-1 component against dog hepatitis. Inactivated vaccine for horses against equine adenoviruses has been prepared in Australia. In farm animals, inactivated bivalent vaccines (containing one mastadenovirus and one atadenovirus) have been in use in several countries for

Transmission and Tissue Tropism

Transmission in outbreaks in daycare centers and nursing homes. Infection may also occur via contaminated water or foods, particularly shellfish. Most human and animal astroviruses are associated with symptoms of gastroenteritis, and replication has been documented in the gastrointestinal tract. A noteworthy exception is duck hepatitis virus which has been detected by EM in the livers of animals with histologic evidence of hepatitis.

Bio Robot Workstations

For the extraction of hepatitis C virus RNA, it was shown that it is possible to achieve a detection level of 12.8 IU mL (95 confidence). Cross-contamination studies have confirmed that the use of the BioRobot 9604 does not pose a detectable contamination risk. 2 For hepatitis B virus detection, Mitsunaga et al. describe that it was possible to quantify DNA in all samples extracted by the BioRobot 9604 which contained more than 500 genome equivalents mL. Extraction of 96 samples could be completed within 2 hr. 3

Preconceptual counselling in the lowrisk setting

Most women in developed countries will be immune, and therefore particular care must be taken to screen immigrant groups. HIV and hepatitis are not normally checked other than in women undergoing fertility treatment or in immunocom-promised groups, though a case can be made for such a check prior to conception. Hepatitis C and varicella may be checked selectively.

Taxonomy and Classification

Early structure analyses of BVDV and CSFV indicated a virion architecture similar to the classic toga-viruses. Since there was no apparent insect vector for these viruses, the term 'nonarthropod-borne toga-viruses' was created to include BVDV, BDV, CSFV, equine arteritis virus, lactate dehydrogenase virus and rubella. With the establishment of the antigenic relationship of BVDV, BDV and CSFV, a new genus, Pestivirus, was created within the family Togaviridae in 1982. Data on the genomic structure of the pesti-viruses indicated a closer relationship to viruses such as yellow fever virus and West Nile virus, and in 1991 the pestiviruses were reclassified in the genus Pestivirus within the Flaviviridae family. Yellow fever virus is in the genus Flavivirus. The hepatitis C group of viruses are also included within this family under the genus 'Hepatitis C-like viruses'.

Dl Particles in Natural Infections

Nevertheless, association of a chicken influenza virus strain, efficiently producing DI particles, with an epidemic of low morbidity and low mortality, and conversely, a high-mortality epidemic associated with a strain free of DI particles, have been reported. Murine and feline leukemia virus strains causing immunedeficiency syndromes are shown to contain predominantly replication-defective viral genomes before onset and during the development of the disease. The pathogenicity of some bovine and swine pestiviruses has clearly been associated with presence of DI RNAs in the animals. For the bovine viral diarrhea virus (BVDV), a pestivirus of the same family as hepatitis C virus, the presence of a particular DI RNA can turn noncytopathic virus into a fatal infectious agent. In plants, at least three examples of DI RNAs are described to be involved in infection modulation. Interestingly, depending on the types of viruses, DI RNAs can either attenuate or exacerbate the symptoms. DI RNAs...

Future Perspectives

See also Bovine diarrhea virus and Border disease virus (Flaviviridae) Chikungunya, O'nyong nyong and Mayaro viruses (Togaviridae) Dengue viruses (Flaviviridae) Encephalitis viruses (Flaviviridae) Tick-borne encephalitis and Wesselsbron viruses Equine encephalitis viruses (Togaviridae) Hepatitis C virus (Flaviviridae) Hog cholera virus (Flaviviridae) Japanese encephalitis virus (Flaviviridae) Rubella virus (Togaviridae) Sindbis and Semliki Forest viruses (Togaviridae).

Gender Ethnicracial And Life Span Considerations

Cirrhosis is most commonly seen in the middle-aged population it is the fourth leading cause of death in the population that is 35 to 55 years of age. It is more common in males than in females. Although the cause is obscure, liver disease appears to be more prevalent in preterm infants who have minimum enteral feedings and who were begun on total parenteral nutrition (TPN) at an early age. Hepatitis C is more common in minority populations, such as African Americans and

Geographic and Seasonal Distribution

Many animal enteroviruses occur worldwide and may be endemic where host populations are sufficient to sustain them. However, the virulent serotype 1 PEV strain, Teschen disease virus, appears to be geographically restricted to parts of Africa and Eastern Europe, whereas the less virulent serotype 1 strains have a global distribution. Swine vesicular disease was first observed in Italy in 1966, since when outbreaks have been reported in most European countries and in Malta, Hong Kong and Japan. The continents of Africa, America and Australia have remained free of the disease. Most outbreaks have occurred in Great Britain, where they have been reported to peak in December and January. Avian encephalomyelitis was first identified in New England in 1932 and the disease has since been confirmed in many countries of the world. Duck virus hepatitis was initially reported in the USA in 1945 and then again in 1949. Since then the disease has spread to many countries in Europe, Asia, North...

Structure and Function

Some RNA viruses, such as the hepatitis delta virus, also include a ribozyme as part of their inherited RNA molecule. During replication of the viral RNA, long strands containing repeats of the RNA genome (viral genetic information) are synthesized. The ribozyme then cleaves the long multimeric molecules into pieces that contain one genome copy, and fits that RNA piece into a virus particle.

Pathology and Histopathology

Macroscopic lesions are seen only rarely as a result of infection by AEV. Histological changes in the central nervous system include lymphocytic perivascular cuffing, evidence of gliosis and axonal-type neuronal degradation. In addition, hyperplasia of the lymphoid follicles in visceral tissue occurs. The livers of ducks suffering from duck virus hepatitis are enlarged and contain hemorrhages. The spleen is often also enlarged and the kidneys may be swollen. Histological signs include hepatic necrosis, varying degrees of inflammatory cell infiltration and proliferation of bile duct epithelium. Gross lesions are observed in the liver and pancreas of turkeys suffering from turkey virus hepatitis. The histological changes include necrotic foci, hemorrhage and mononuclear foci. Focal parenchymal foci of necrosis may also be observed in the pancreas.

Discharge And Home Healthcare Guidelines

Teach the patient and significant others about the disorder and that it is unlikely that it will recur in the future. If the patient required blood component therapy, provide information about the risk of hepatitis or human immunodeficiency virus (HIV) transmission. Check with the patient's obstetrician to determine if the patient can nurse the infant and resume unprotected sexual relations. Provide discharge instructions related to the patient's primary diagnosis. Teach the patient to notify the physician of any uncontrollable bleeding or syncope.

Clinical Features of Infection

Most HBV infections are asymptomatic with mild serum alanine aminotransferase (ALT) changes that resolve, although clinically apparent acute hepatitis and occasionally fulminant hepatitis with hepatic failure and death can occur. The severity of acute viral hepatitis B appears to be related to age of infection (young children generally have milder disease than adults), the infecting virus dose (higher doses appear to result in shorter incubation period and generally more severe hepatitis), and immunosuppression which may be associated with mild disease and frequent persistent infection. Chronic HBV infection is most often asymptomatic ('healthy carriers') and symptomatic chronic active hepatitis with periods of fever, malaise and hepatic pain is much less common. In highly endemic regions of the world such as eastern Asia, most HBV infections occur in newborns or young children and are relatively asymptomatic many of these infections become persistent and remain silent for many years...

Prevention and Control

HBV infections are prevented by measures that interrupt routes of transmission. Recognizing and identifying HBV-infected individuals permits avoidance of contacts which may lead to transmission. Changes in behavior with respect to sexual contacts and illicit intravenous drug use can reduce spread of HBV. Elimination of infected blood and plasma donors by HBsAg screening has largely eliminated HBV infections by blood transfusion and by other blood products. Screening all pregnant women for HBsAg permits protection of newborns of infected mothers by use of hepatitis B immune globulin and HBV vaccination (such passive-active immunization protects up to 95 of newborns of HBV-infected mothers).

Hare Fibroma Virus see Poxviruses

Nassal M (1996) Hepatitis B virus morphogenesis. Curr. Top. Microbiol. Immunol. 214 297. Seeger C and Mason WS (1996) Replication of the hepatitis virus genome. In dePamphilis E (ed.) DNA Replication in Eukaryotic Cells, p. 815. Cold Spring Harbor Cold Spring Harbor Laboratory Press. Avian Hepatitis B Virus

Properties of the Proteins

Hepadnaviruses produce a large excess of the envelope proteins, above the amount needed for virion assembly, and the excess is secreted as surface antigen particles. The S protein appears to be sufficient for production of surface antigen by orthohepadnaviruses, though L can also be incorporated into these particles. Both L and S have been detected in surface antigen particles produced by duck hepatitis B virus, the prototype avihepadnavirus. The surface antigen particles produced by avihepadna-viruses are pleomorphic spheres, 40-60 nm in diameter, whereas orthohepadnaviruses produce regular, 22 nm diameter rods and spheres. The particles produced by the orthohepadnaviruses may have a much lower lipid content than those produced by the avihepadnaviruses, and in neither case has the mechanism of assembly been determined, although, as for the virions, the particles first appear in the cisternae of the endoplasmic reticulum. Figure 2 The replication of duck hepatitis B virus within...

Host Range and Virus Propagation

Duck hepatitis B virus infects wild mallards and related domestic ducks (Anas platyrhynchos). Transmission to the Muscovy duck and the chicken has not been successful, but the virus can be transmitted to domestic Embden and Toulouse geese and has also been detected as an apparently natural infection in domestic geese. The distribution of duck hepatitis B virus in geese and other waterfowl has not been studied in detail. The virus is not known to be infectious to mammals. The virus will infect and replicate in primary duck hepatocyte cultures, and can be transmitted to developing duck embryos. In vivo, hepatocytes produce infectious virus, which is released into the bloodstream, producing a persistent viremia in the chronic carrier. The apparently limited host range of duck hepatitis B virus is probably due to a lack of cell surface receptors for the virus in nonsusceptible species. Indeed, the virus will replicate efficiently in a chicken hepatocellular carcinoma cell line transfected...

Serologic Relationships and Variability

There are currently no defined subtypes or serotypes of duck hepatitis B virus, though there are monoclonal antibodies which distinguish between different amino acid sequences of the surface antigen. The amount of variation in nucleotide sequence in the published sequences of duck hepatitis B virus (1.2 11.6 ) appears to resemble that of hepatitis B virus subtypes (8 10 ). Sequences from three genomes cloned from ducks from the USA and Germany appear more closely related to each other (1.2-5.9 variation) than to five sequences cloned from ducks Five sequences of heron hepatitis B virus have been published. Up to 7 sequence diversity has been found in the heron hepatitis B virus isolates. The prototype heron hepatitis B virus sequence differs from duck hepatitis B virus sequences by 21.6 , somewhat more than the 16.4 variation between the woodchuck and ground squirrel hepatitis viruses.

Properties of the Viral Proteins

The four protein-coding regions of the mammalian hepadnaviruses are translated into seven known proteins (Fig. 1). The core ORF codes for the 21 kDa viral capsid protein, also called hepatitis B core antigen (HBcAg) and the 16-18 kDa precore polypeptide, termed hepatitis B e-antigen (HBeAg). The HBcAg is the most highly conserved polypeptide among the mammalian hepadnaviruses showing 68 amino acid homology between HBV and GSHV (GSHcAg) and 92 between GSHV and WHV (WHcAg). It is a cytoplasmic and nuclear phospho-protein with a basic C-terminus that is essential for the packaging of viral RNA. Core polypeptide monomers form dimers that assemble into spherical shells with icosahedral symmetry consisting of 120 dimer subunits. The formation of these dimers is mediated by two long alpha helices that form spikes on the surface of nucleocapsids. Dimers are further stabilized through the formation of two homologous intermolecular disulfide bridges.

Pathology and Histopatholgy

The histologic changes in acute and chronic hepatitis C cannot generally be differentiated from those occurring in other types of viral hepatitis. The histologic changes in the liver during acute viral hepatitis are hepatic inflammation and hepatocellular necrosis. Inflammatory cells, principally lymphocytes and macrophages, are present in both the parenchyma and portal areas. Swelling and eosinophilic necrosis of hepatocytes are common. Chronic hepatitis C is characterized by inflammation (lymphocytes, macrophages and histiocytes) that is largely portal in distribution and hepatocellular necrosis that is typically periportal.

Geographic Distribution

Hepatitis delta virus infection is found worldwide and is endemic in certain areas, particularly southern Italy and the Mediterranean countries. Its distribution closely parallels that of HBV infections. However, its prevalence rate does not always match that of HBV infection in different geographical areas for example, in some HBV-prevalent areas such as China, HDV infection is disproportionately low. In developed countries such as the USA, the rate of HDV infections is low in the general population and highest among intravenous drug abusers and hemophiliacs who receive blood products. Genotype I HDV has been isolated in every geographical region in the world. Genotype II so far has been found largely within Asia, primarily Taiwan and Japan. Genotype III, which is associated mostly with fulminant hepatitis, has been detected only in South America.

Prevention and Control of Infection

Because HDV infection is dependent on a concomitant HBV infection, control of HDV infection is best achieved by HBV vaccination. However, there is no effective measure to prevent HDV infection of chronic HBV carriers. No routine blood screening for HDV is currently performed however, HDV infection by contaminated blood sources can be prevented by screening for HBV. Currently, there is no specific treatment for delta hepatitis. Interferon a has been tried therapeutically with only marginal and transient effects. Ribavirin has been shown to inhibit HDV RNA replication in tissue culture.

Molecular Biology of Genome Structure

Epitope mapping using a strategy of overlapping peptides revealed the presence of several potential immunogenic peptides, especially in the polymerase region. However, none has been shown to be of use in diagnostic assays. ORF 2 occupies the 3'-most 2 kb of viral genomic sequence and codes for the single capsid protein of HEV. A hydrophilic electropositive region rich in arginine residues found near the N-terminus of the capsid protein serves to neutralize and encapsulate the electronegatively-charged genomic RNA. A major immunogenic epitope is located at the C-terminus of the capsid protein, and has been found to be most useful in the diagnosis of hepatitis E (see below). The small ORF 3 also codes for an immunogenic protein of 123 amino acids however, its biological role in the life cycle of the virus remains unclear.

Classification and Properties

Caliciviruses were initially classified as picornaviruses with which they share a number of properties. However, the distinctive properties of caliciviruses led to the creation of a new family Caliciviridae. Human hepatitis E virus was originally considered to be a calicivirus because of apparent similarity in morphology but is now classified in the genus Hepevirus in an undefined family.

Physical Properties

The resistance of HCV to physical and chemical treatment is partly dependent on the physical state of the material containing the virus. For instance, in cell culture fluid the virus is inactivated more rapidly than in defribinated blood. The mean inactivation rate at 56 C was found to be between 1.6 and 2.7 log units in 30 min. Below pH 4 and above pH 11, viral infectivity is quickly lost. Because the virion envelope contains lipids, solvents such as chloroform and ether easily inactivate HCV. In pork, the virus remains infectious for months, whereas in the environment outside the host the virus is usually inactivated in a couple of days however, in liquid pig manure, HCV may survive for 2 weeks at 20 C and more than 6 weeks at 4 C. For disinfection, 1-2 sodium hydroxide is most suitable.

Serological Relationships and Variability

Although there is antigenic variation among HCV strains, they belong to one antigenic group, as shown by extensive crossneutralization with polyclonal antisera. The antigenic variation appears to reside on the antigenic unit on the N-terminal half of E2, as well as on El. Within strains, with the use of monoclonal antibodies directed against E2, antigenic heterogeneity is observed as well. There is a clear-cut distinction between HCV and BVDV, but these viruses are antigenically closely related, as shown by various serological techniques, including immunodiffusion and neutralizing antibody tests. In addition, there is a certain degree of cross-protection, i.e. pigs given a BVDV strain can be protected against mortality, but not disease, due to HCV. The common antigens among pestiviruses reside largely on the nonstructural protein NS2.3.

Transmission and Tissue TVopism

Pigs are infected via the oronasal route. The tonsil is the primary target tissue for virus replication. The spread of high-virulent HCV through the pig is characterized by lymphatic, viremic and visceral phases. The virus primarily replicates in epithelial cells of tonsillar crypts and then invades the underlying lymphoreticular tissues. Through the lymphatic capillaries the virus is carried to lymph nodes and, after replication in these nodes, it enters the efferent blood capillaries, giving rise to a high-titered viremia. It subsequently replicates to high titers in secondary target organs, e.g. spleen, visceral lymph nodes, lymphoid structures lining the intestine and in bone marrow. It is presumably late in the viremic phase, which persists till death, that HCV invades the parenchymatous organs. Generally, the virus titers are higher in lymphoid tissues than in parenchymatous organs. The virus has an affinity for vascular

Primary Nursing Diagnosis

Replacement therapy and drug therapy may be used prophylactically or to control mild or major bleeding episodes. Desmopressin will raise factor VIII levels two- to threefold. Factor VIII replacement therapy is indicated for active bleeding or preparation for multiple tooth extractions or major surgery. Cryoprecipitate contains high levels of factor VIII and fibrinogen. Purified plasma-derived factor VIII concentrates are derived from large pools of plasma donors. Recent methods of screening and heating of these concentrates have greatly diminished the risk of contamination with the human immunodeficiency virus (HIV) but have little effect on the risk of hepatitis transmission. High-potency factor VIII preparations (those that are highly purified) are considered to be virtually virus-free. Recombinant factor VIII contains less risk of viral transmission but has a relatively high cost. A rule of thumb is that for every 1 unit kg infused, factor VIII levels will increase 2 . In an...

Estimation Of Infectivity

Another important reason for HBV viral load determination is the assessment of the infectivity of hepatitis B carriers. Without intervention, more than 90 of HBeAg-positive female chronic HBV carriers transmit the virus to their infants 17 of these, 85-90 develop chronic HBV infection in most cases asymptomatic themselves, thus perpetuating the infection in high-endemicity settings. Immediate postpartum immunization of the infant can efficiently prevent transmission. It has to be considered that the level of viremia present in maternal serum can only be approximated with the HBeAg assay. Recent quantitative evaluation of sera for HBV DNA using molecular hybridization technology has shown that wide fluctuations in the concentration of virus exist in HBeAg-positive carriers. Vertical transmission is rarely documented with maternal HBV DNA levels below 107 geq mL (5 pg mL). 18,19 In a recent study, no cases of trans-placental transmission of HBV were observed with maternal HBV DNA levels...

Methods of induction of labour with a favourable cervix [6

Urgency of the labour induction, oxytocin infusion may be started with the amniotomy or may be used only if progress after amniotomy is inadequate. Because of the considerable variability in sensitivity of the myometrium to oxytocin, oxytocin is administered as a variable dose infusion, titrated against uterine contractions. A typical dosage schedule would be 1 mU min, doubling the rate of infusion every 20-30 min until adequate uterine contractions are achieved or a rate of 32 mU min is reached. Once labour is established the infusion rate may be progressively reduced, as the myometrial sensitivity increases, to a rate of about 7 mU min. Amniotomy should be avoided if the woman is not known to be free of infections such as HIV and hepatitis, in which case oxytocin infusion may be used with intact membranes.

Other Keratin Disorders

Recent studies have revealed that mutations in keratins expressed in simple epithelia may be involved in the pathogenesis of a number of gastrointestinal diseases. 20 Cryptogenic cirrhosis is a diagnosis of exclusion applicable to an individual with cirrhosis who does not carry a hepatitis B or C virus who does not test positive for serological markers associated with autoimmune hepatitis or primary biliary cirrhosis who has normal iron, ceruloplasmin, and aj-antitrypsin levels and who has no history of alcohol or toxin ingestion. Recurrent mutations in human K8 K18 genes have been shown to predispose individuals to cryptogenic cirrhosis, chronic pancreatitis, and inflammatory bowel disease. 20,34,35 How K8 K18 mutations cause liver disease is still a matter of debate. Animals deficient in K8 K18 are highly susceptible to proapoptotic signals, suggesting that keratins may play a cytoprotective role in the gastrointestinal tract. 20

As Comprehensive Gene Expression Profiling

The clinical challenges mentioned above point to a need to understand in a comprehensive fashion the underlying molecular mechanisms of kidney cancers. One recent biomedical breakthrough is the use of high-throughput microarray technology, which allows comprehensive gene expression profiling of tumors. These gene expression profiles can serve as the molecular signatures of particular tumors, and they may be used to distinguish among histological subtypes and novel distinct subtypes that are correlated with clinical outcome. This distinction may reflect the heterogeneity in transformation mechanisms, cell types, or aggressiveness among tumors. For example, approx 100 genes were identified as differentially expressed by serous as compared to mucinous ovarian cancers (27). Other studies have identified distinct gene sets that distinguish between acute myeloid leukemia and acute lymphoblastic leukemias (28), between hereditary breast cancer with BRCA1 and BRCA2 mutations (29), and between...

NS2 is a cysteine protease

Catalysis of a peptide bond by cysteine proteases proceeds through a well-characterized, charge relay network mechanism. The NS2 structure suggests that Glu 163 polarizes His 143 to deprotonate the cysteine side chain. The nucleophilic Cys 184 attacks the carbonyl of the scissile bond forming a negatively charged, tetrahedral transition state. Cleavage of the activated intermediate releases the N terminus of NS3 and creates an acyl-enzyme intermediate in which Cys 184 is covalently bonded to Leu 217. Hydrolysis of the acyl-enzyme intermediate forms the carboxylic acid of Leu 217 and restores the proton to Cys 184. Interestingly, Pro 164, which is adjacent to Glu 163 of the catalytic triad, has a c s-peptide conformation with the pyrrolidine ring lying on the same side as the carbonyl group of Glu 163 (Fig. 6). This proline residue is entirely conserved in HCV and the related GB virus sequences, implying that this position has an important

Viruses Affecting the Heart

Commonly e.g. enteroviruses, human immunodeficiency virus (HIV) and, if acquired congenitally, rubella whereas others are uncommon e.g. varicel-la-zoster, cytomegalovirus (CMV) and hepatitis B . Many of these viruses involve the heart as part of a clinically obvious generalized infection (e.g. varicella, mumps and rabies) whereas in others, cardiac disease is the primary presenting clinical feature. The more common causes of viral heart disease are discussed below, but some of those occurring less commonly are listed in Table 1.

Evidence in favor of a NS2 dimer

A series of experiments in mammalian cells was designed to test whether NS2pro can form dimers with a functional composite active site in vivo. HCV full-length polyproteins containing either a H143A or a C184A mutation in the NS2 active site are defective in NS2-3 processing.1314 However, if a composite active site can form, co-expression of the two. mutant polyproteins should result in partial NS2-3 cleavage (see figure 3 in ref 27). Indeed, when HCV polyproteins with NS2 containing either a H143A or C184A mutation were co-expressed, NS2 and NS3 cleavage products were detected, indicating the formation of a functional composite active site. These data strongly support the NS2pro crystal structure and prove that NS2 can form dimers with composite functional active sites.

Commercial Application

Transgenic microbes have many commercial and practical applications, including the production of mammalian products. A company called Genentech was among the earliest and most successful commercial enterprises to use genetically engineered bacteria to produce human proteins. Their first product was human insulin produced by genetically engineered Escherichia coli. A variety of other human hormones, blood proteins, and immune modulators are now produced in a similar fashion, in addition to vaccines for such infectious agents as hepatitis B virus and measles.

DI Particles in Natural Infections

Nevertheless, association of a chicken influenza virus strain, efficiently producing DI particles, with an epidemic of low morbidity and low mortality, and conversely, a high-mortality epidemic associated with a strain free of DI particles, have been reported. Murine and feline leukemia virus strains causing immune deficiency syndromes are shown to contain predominantly replication-defective viral genomes before onset and during the development of the disease. The pathogenic-ity of some bovine and swine pestiviruses has clearly been associated with presence of DI RNAs in the animals. For the bovine viral diarrhea virus (BVDV), a pestivirus of the same family as hepatitis C virus, the presence of a particular DI RNA can turn noncytopathic virus into a fatal infectious agent. In plants, at least three examples of DI RNAs are described to be involved in infection modulation. Interestingly, depending on the types of viruses, DI RNAs can either attenuate or exacerbate the symptoms. DI RNAs...

Diagnostic Highlights

Viral hepatitis seriologies hepatitis A virus (HAV) hepatitis B virus (HBV) hepatitis C virus (HCV) hepatitis D virus (HDV) hepatitis E virus (HEV) (See Hepatitis, p. 410) If patient has hepatitis acute HAV positive anti-HAV IgM acute HBV anti-HBV IgM HB surface antigen acute HCV anti-HCV antibody, HCV RNA HDV anti-HDV IgM, HDV antigen HEV not available Non A Non B all tests negative Identify patients with hepatitis virus leads to markers such as immunoglobulins (IgG and IgM), antigens, antibodies

High Purity pdFIX Products

The use of enzyme replacement therapy (ERT), through administration of PCCs and pdFIX products, to treat hemophilia has no doubt enhanced the quality of life of the numerous recipients over the years, but has come at a considerable cost to many individuals receiving ERT. Numerous incidents from around the globe of HIV and hepatitis virus transmission through contaminated blood-clotting factor concentrates for hemophilia treatment have been reported 6,38-40 . Consequently, viral inactivation steps (Section 11.4.2.1) were introduced in the mid-1980s to eliminate the risk of transmission of HIV and hepatitis diseases. Although HIV, hepatitis viruses, and other enveloped viruses have not been transmitted since the introduction of these viral inactivation steps, concern remains about the possibility of nonenveloped viruses (such as parvovirus and hepatitis A) being transmitted 41,42 .

Steps to Increase Safety of Blood Derived Clotting Factor Products

Screening plasma for HIV, hepatitis (A, B, and C), parvovirus B19, syphillis, and cytomegalovirus is now a routine and standard practice. Traditionally, this was performed using enzyme-linked immunosorbent assay (ELISA) testing, an extremely sensitive method for detecting pathogens 42 . More rapid and sensitive nucleic acid amplification testing (NAT) has been introduced in most North American and European countries since the late 1990s. NAT offers an increased margin of safety for clotting factor concentrates 41 , in that it enables detection of hepatitis A and parvovirus, both of which are relatively recalcitrant to many viral inactivation technologies (see below). 3. Viral inactivation steps. Heat treatment was first introduced as a virucidal measure in the mid-1980s. Viruses have varying thermal sensitivities, with viruses such as HIV being more susceptible to heat treatment than the hepatitis viruses 41,43 . Heat treatment can result in significant denaturation of...

Global and International Surveillance

International surveillance can also be used for the detection of international outbreaks of food poisoning caused by the distribution of foodstuffs across a wide number of countries. An outbreak of hepatitis A in England was caused by frozen raspberries grown and frozen in another country and another outbreak of hepatitis A, this time in Czechoslovakia (before it became separate republics) was caused by strawberries used to make ice cream the strawberries had been imported from another Eastern European country. There are now well-established trans-European surveillance systems for salmonella infections and legionnaires' disease.

Neonatal Immunization

Induce immunity in neonates in the presence or absence of maternal antibodies makes this approach to vaccination extremely attractive, especially for diseases such as herpes simplex virus-2, human immunodeficiency virus (HIV), hepatitis B, group B strep, and chlamydia which often infect children during birth or shortly thereafter.

Clinical Manifestations

In neonates, a severe generalized infection, often clinically indistinguishable from bacterial sepsis, can include meningitis or meningoencephalitis, myocarditis, and hepatitis. A similar syndrome is caused by echoviruses and coxsackie B viruses. The transmission occurs transplacen-tally or soon after delivery from the mother but can also originate from other infected infants. Immunocompro-mised patients may develop serious chronic echovirus infections, like meningoencephalitis, occasionally with fatal outcome. These complications occur in individuals with B-cell deficiencies and gammaglobulin has been used for the prevention and treatment of the infections.

Enterohepatic Bile Acid Transporters In Liver Disease

No mutations in the SLC10A1 gene encoding NTCP leading to clinically manifest defects in hepatic bile acid uptake have been characterized thus far. However, a recent study identified ethnicity-dependent single-nucleotide polymorphisms in the SLC10A1 gene that were associated with a considerable decrease in transport function in vitro.39 Thus, genetic heterogeneity in the SLC10A1 gene may play a role in the etiology of hypercholanemia. Furthermore, certain human diseases, such as advanced stage primary biliary cirrhosis40 and cholestatic alcoholic hepatitis,41 are associated with reduced NTCP expression. However, this change in NTCP expression may be a consequence of cholestatic liver injury rather than a cause of it.

Pathological features

Depending on the results of the laboratory tests, those patients meeting the criteria above are classified into groups listed below. The following studies are suggested complete blood count, erythrocyte sedimentation rate, chemistry profile, creatine kinase, antinuclear antibody, thyroid functions, serum and urine immunoglobulin studies (to include either immunofixation electrophoresis or immunoelectrophoresis, and HIV and hepatitis serology. The list of laboratory studies is not comprehensive. For instance, in certain clinical circumstances, other studies may be indicated, such as phytanic acid, long-chain fatty acids, porphyrins, urine heavy metals, a-lipoprotein, p-lipoprotein, glucose tolerance test, imaging studies of the central nervous system, and lymph node or bone marrow biopsy. Classification of CIDP

Genome Organization

As noted above, all hepadnaviruses have a similar genome organization, despite the low DNA sequence identity between the mammalian and avian hepadnaviruses (40 ). The negative strand of the DHBV genome contains S-ORF, C-ORF, and P-ORF encoding the surface or envelope proteins, core and e antigen proteins, and polymerase protein, respectively (Figure 1). The DHBV genome was originally thought to contain only these three ORFs and to lack an ORF encoding a protein analogous to the X protein of the mammalian hepadnaviruses. It was subsequently discovered that avian hepadnaviruses, including HHBV and DHBV, have a fourth ORF, the X-ORF, which directs synthesis of a candidate X protein that is translated using an unconventional start codon. The significance of this observation is still unclear. Using woodchuck hepatitis virus (WHV), a close relative of HBV, the X gene was shown to be essential for successful WHV infections in vivo. In contrast, knockout of the X gene of DHBV did not alter...

Phylogenetic Information

Assigned species within the genus Avihepadnavirus include DHBV isolated from Pekin ducks (Anas domesticus) and HHBV from grey herons (Ardea cinerea). Many DHBV isolates have been found in domesticated ducks and, in the wild, in the mallard, the species from which most domesticated ducks are derived. Viruses less closely related to DHBV have been isolated from geese and other duck species and include the Ross's goose hepatitis B virus (RGHBV) from Ross's geese (Anser rossii), Mandarin duck hepatitis B virus (MDHBV) from Mandarin ducks (Aix galericulata), and the snow goose hepatitis B virus (SGHBV) from snow geese (Anser caerulescens). The stork hepatitis B virus (STHBV) has been isolated from white storks (Ciconia ciconia), with additional viruses isolated from demoiselle (Anthropoides virgo) and grey crowned cranes (Balearica regulorum) (Figure 4). By genome sequencing, HHBV and STHBV are the most distant from DHBV (Figure 4). HHBV was assigned as a species based both on genome...

Multiplex Nasba And

The Procleix human immunodeficiency virus-1 hepa-titis C virus (HIV-1 HCV) assay (Gen-Probe Inc.) detects both HIV- and HCV RNA in 1 tube. 8 The source of the reactivity can be determined by discriminatory assays using virus-specific probes. The HIV-1 HCV assay and the discriminatory assays are able to detect 10-13 copies of HIV-1 mL with 95 detection rates, and can detect 30 copies mL of HCV with 95 sensitivity. Furthermore,

Quantitative Nasba And Tma Applications

Quantitative nucleic acid amplification tests are gradually introduced into the laboratory. These assays are used for determination of the viral load of patients infected with blood-borne viruses such as human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). The conserved 5'NCR of HCV has been used as a target for the development of qualitative and quantitative ECL-based NASBA assays for genotypes 1a, 1b, 2, 3, 4, and 5. 16 When different assays were compared, the HCV NASBA-QT assay was over 10 times more sensitive than the bDNA assay, while the quantitative results of both assays were highly concordant. The HCV NASBA- QT assay was comparable in sensitivity with the HCV MONITOR assay (Roche Molecular Systems), but the latter yielded consistently lower values. 16 The qualitative COBAS AMPLICOR HCV version 2.0 PCR assay (Roche Molecular Systems) and the VERSANT HCV RNA qualitative assay (Bayer) were compared for analytical sensitivity and clinical perfor-mance. 17 The...

Replication And Infectivity

Mousepox (ectromelia) virus was first recognized as a mouse pathogen in 1930. Its pathogenesis differs from other orthopox viruses in that the virulent strains induce severe hepatitis in mice. It is highly infectious and can easily decimate mouse colonies in laboratories and breeding facilities. Vaccinating mice with the Vaccinia confers protection and has been used to control infections in mouse colonies. 7 No human infections have been reported due to ectromelia. However, the virus was useful as model to study the molecular basis of Orthopoxvirus virulence despite the fact that the mouse disease differs significantly from smallpox.

Multiple Biological Implications

The frequency of antibody-resistant mutants of RNA viruses is generally high (10 4-10 6 per infectious genome) both in cell culture and in vivo. The frequency of cytotoxic T lymphocyte-escape mutants is more difficult to determine but variations at specific T cell epitopes permitting virus escape in vivo have been documented in several systems, such as human hepatitis C virus, human immunodeficiency virus and lymphocytic choriomeningitis virus. Recent evidence suggests that the complexity of the mutant spectrum may influence the outcome of viral infections. The complexity of the coronavirus mouse hepatitis virus quasispecies may contribute to its pathogenic potential. Likewise, the nonresponse to treatment with interferon a in chronic hepatitis C virus infections may relate to the number of viral molecular species detected in the infected patients. Model experiments with the animal pathogen foot-and-mouth disease virus showed that indeed the repertoire of viral mutants that became...

Recombination in RNA Viruses

Sequence rearrangements were found in the following animal plus-strand RNA viruses picorna-viruses poliovirus and foot-and-mouth-disease virus (FMDV) in coronaviruses mouse hepatitis corona-virus (MHV) Sindbis alpha virus (SIN) flock house nodavirus (FHV) and in bacteriophages Q , and MS-2. Recombinants were found in bunyaviruses. Genetic rearrangements were also observed in other types of RNA viruses, including influenza virus, a minus-strand RNA virus, in retroviruses, and in double-stranded 06 bacteriophage. The following genomes of plant RNA viruses reveal RNA rearrangements alfalfa mosaic virus (AlMV), beet necrotic yellow vein virus (BNYVV), bromoviruses (see below), hordei-viruses, luteoviruses, nepoviruses, tobamoviruses, tobraviruses, tombusviruses and turnip crinkle car-movirus (TCV).

Never Ending Adaptation

Not all RNA virus populations show this dynamic of a continual change or even the diversity expected from quasispecies. Even in influenza virus A, avian isolates from natural host (waterfowl) can be genetically stable. Some RNA (and retro) viruses with high error rates can nevertheless maintain stable populations in specific hosts. For example, measles virus shows much less antigenic drift in human infections compared to influenza virus A. Hepatitis G virus (a human prevalent and distant relative of HCV) shows little variation in even isolated human populations. The filoviruses (Ebola virus and

Ligands Bound to Structured RNA

Similar methods have been applied to drug discovery efforts directed toward the 5'-UTR region of the hepatitis C virus (HVC) genomic RNA. This region contains a highly conserved structured RNA shown to be crucial for viral replication and translation, presumably by serving as an internal ribosomal entry site (IRES). Screening of a library of compounds for binding to a particular subdomain of the HCV IRES led to the identification of a hit having relatively weak affinity and modest selectivity for the target RNA. Using an MS-guided chemical optimization approach, this weak hit was elaborated into a lead structure which had sub-micro-molar affinity for the target RNA and activity in a cellular assay 28 .

Serological Relationship and Variability

Thus, many serotypes seem to coexist within the human population. The multiplicity of serotypes is in contrast to two other medically important picornaviruses, the polioviruses (three serotypes) and hepatitis A virus (a single serotype). Several serotypes fall into groups on the basis of low-level immunological crossreactivity with hyperimmune serum (HRV-36, HRV-58 and HRV-89 HRV-2 and HRV-49 for example), but it is not known whether this plays any role in protection from heterologous serotypes. These antigenic groups seem to correlate with close molecular relationships (Fig. 3).

Is DNA Hypomethylation Like DNA Hypermethylation Sometimes Associated with Tumor Progression

Hypermethylation of a subset of CpG islands is progressive in some types of cancer although sometimes this regional hypermethylation occurs very early in tumorigenesis, and other times it can serve as a significant indicator of survival.16,82, 3 Also, DNA hypomethylation is sometimes associated with tumor progression as seen in studies of repeated DNA sequences. In a study of 31 hepatocellular carcinomas by Itano and coworkers,84 the degree ofhypomethylation of either of two repetitive sequences was significantly correlated with postoperative recurrence of hepatocellular carcinoma and was a better predictor than conventional factors. These repeats were the above-mentioned 1.4-kb Y10752 NBL2 sequence that is found in the pericentromeric regions of chromosomes 13, 14, 21, and 950 and a 13-kb repeat present in tandem about 200 times on 8q21. Hypomethylation was determined by quantitating the corresponding radioactive spots relative to reference spots by restriction landmark genomic...

Genetics and Evolution

Since their are no known animal relatives of rubella virus, the origin of the virus prior to its introduction into the human population is unknown. Rubella virus and the alphaviruses share no nucleotide homology except for short stretches at the 5' end of the genome and at the subgenomic promoter site. Thus these two genera are only distantly related. Rubella virus and the alphaviruses both belong to the 'alphavirus-like superfamily' of plus-sense RNA viruses which includes a large number of plant viruses as well as human hepatitis E virus, which is currently classified as a calicivirus. Within this superfamily, computer-assisted phylogenetic analysis of the nonstructural

Satellite Rnas And Satellite Viruses

By helper viruses for their accumulation. However, some RNA molecules which are not required by the helper virus for experimental infection, appear to be essential for the natural life cycle of the virus, by contributing to vector transmissibility. Such examples are the RNAs associated with groundnut rosette virus (GRV) and beet necrotic yellow vein virus (BNYVV), which have been described and are referred to as satellite-like RNAs. A related group of subviral agents is that containing RNAs that resemble satellites but which depend on a helper virus only for encapsidation rather than for replication e.g. hepatitis delta virus (HDV) and beet western yellows virus (BWYV) ST9-associated RNA .

Structure and Replication

The pestivirus genome is c. 12.3 kbp, with variant genomes of larger and smaller size generated by recombination events (Figure 3). Pestivirus genomes lack a 5' cap structure, and translation is mediated by a 5' internal ribosome entry site (IRES) element that has similarities to the hepatitis C virus (HCV) IRES. The 3' UTR contains a short polyC tract, as well as variable and conserved regions, the latter of which encodes hairpin structures. The open reading frame codes for 4000 amino acids, and is processed into at least 12 mature proteins Npro, C, Erns, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Npro is a unique N-terminal leader autoprotease, which is followed by the four structural proteins C, Erns, E1, and E2. Erns, which is not found in other viruses of the family, is a heavily glycosylated protein that is secreted from cells and exhibits a ribonuclease activity and a lymphocyto-toxic activity that is involved in pathogenesis. E1 and E2 are integral membrane proteins...

History and Classification

After serologic screening tests for the detection of hepatitis B and hepatitis A viruses were introduced in the 1970s to eliminate these viruses from human blood supplies, the role of HCVs in causing up to 90 of transfusion-associated hepatitis was recognized. The term hepatitis C virus (HCV) was coined in 1989 after identification of an RNA genome of this virus from cDNA libraries of human serum containing the infectious agent. In humans, infection with HCV commonly evolves into a chronic persistent hepatitis which can lead to progressive hepatic cirrhosis and hepatocellular carcinoma. Lack of a suitable cell culture system for propagating HCV had until only recently been a major impediment to progress in understanding the details of its replication. In addition, studies of HCV pathogenesis have been hampered by the lack of animal model systems, and progress has depended on use of clinical data from human cases, or from the use of a chimpanzee model. c. 30-35 , 20-25 , and 1-10 ,...

Epidemiology and Clinical Disease

It is estimated that there are at least 170 million chronically infected HCV subjects worldwide, with prevalence varying from 0.1 to as high as 18 (Egypt). In areas where HCV has been eliminated from blood supplies by donor screening, use of illicit injectable drugs remains the most important mode of transmission. Various other forms of exposure, including occupational and sexual exposures, are involved in some cases of transmission. HCV is a primary cause of cirrhosis, a significant cause of hepato-cellular carcinoma, and in the United States is the leading reason for liver transplantation. There is great variability in the spectrum of disease. Acceleration of disease is observed in persons who are older at the time of infection, and in the setting of continuous alcohol exposure, and co-infection with HIV or hepatitis B virus (HBV). Individuals who sustain infection at a younger age tend to have slower progression. Genotypes 1, 2, and 3 are found worldwide, but with regional...

Diagnosis and Treatment

Diagnosis of chronic hepatitis C infection is established by screening enzyme immunoassay to detect circulating antibodies to HCV proteins, followed by confirmatory determination of HCV RNA in serum, using qualitative and quantitative tests based on target (RT-PCR and transcription-mediated amplification) and signal amplification (branched DNA (bDNA)) techniques. Quantitation of serum HCV RNA helps to identify patients likely to benefit from treatment and undergo virus clearance as defined by a sustained viral response (SVR). Determination of the HCV genotype guides treatment decisions, as genotypes 1 and 4-6 are less amenable to treatment than are genotypes 2 or 3. Therapeutic trials have shown that combinations of interferons and ribavirin are more effective than is interferon alone and pegylated (long-acting) interferons have yielded improved SVR rates. An SVR is less common in patients with genotype 1 infections, high pretreatment HCV RNA levels, or advanced stages of fibrosis....

Application for Other Organisms

Pseudomonas aerugenosa. 24 Furthermore, ribotyping has been applied successfully in many studies to differentiate bacterial strains. 25,26 Other applications of locus-specific RFLP found place in epidemiological studies of hepatitis C virus (HCV). By this technique, the virus can be subtyped into six major genetical groups. 27 The RFLP of the 5' untranslated region has facilitated studies of the geographical distribution of viral genotypes and natural history of the disease.

Medical Management of Terrorist Related Injuries

Of patients with urgent and salvageable life-threatening injuries (undertriage) (Frykberg 2004 Kluger 2003 Stein and Hirshberg 1999). In these circumstances, prioritization of treatment regimens is mandatory and definitive therapy should be delayed until the patient is hemodynamically stabilized damage control principles should be applied. However, identifying those critically injured patients who are candidates for damage control maneuvers, which aims to achieve hemostasis and prevent uncontrolled spillage of bowel contents and urine, is undoubtedly a challenge. Throughout the management of the event, coordination between the primary on-scene teams responsible for the primary triage and evacuation is obligatory, followed by similar close interaction between the in-hospital teams conducting the triage, the initial treatment, the surgical interventions and the intensive care, as well as between neighboring hospitals, in order to optimize utilization of the hospitals' personnel and...

History of Virus Classification and Virus Nomenclature

Virus classification is a relatively new exercise, as the first evidence for existence of a virus was only presented at the end of the nineteenth century by Beijerinck in 1898. It was not until 1927 that Johnson, a plant virologist, drew attention to the need for a system of virus nomenclature and classification. First efforts to classify viruses utilized a range of ecological and biological criteria, including pathogenic properties in the case of human and animal viruses, and symptoms for plant viruses. For example, viruses sharing the pathogenic properties causing hepatitis (e.g. hepatitis A virus, hepatitis B virus, yellow fever virus, and Rift Valley fever virus) were grouped together as 'the hepatitis viruses'. Virology developed substantially in the 1930s and early classifications for the viruses reflected these advances. In 1939, Holmes published a classification of plant viruses dependent on host reactions and differential host species, using a binomial-trinomial nomenclature...

Clinical manifestation

Main identifiable causes drug induced, such as angiotensin-converting enzyme inhibitors, penicillin, sulfonamides, fluoxet-ine, and thiazides rheumatic diseases, such as lupus erythematosus and Sjogren syndrome viral diseases, such as hepatitis B, hepatitis C, and infectious mononucleosis hypocomplementemia occurs in patients with associated systemic diseases, such as systemic lupus erythematosus regardless of cause, disease tends to run chronic cours

Introduction Concepts in RNA Virus Evolution

Foot-and-mouth disease virus (FMDV) is one of the prototypes of anti-genically variable virus, reflected in seven serotypes (A, O, C, Asia 1, SAT1, SAT2, SAT3), and many subtypes and variants, too numerous to be amenable to any reasonable cataloguing at present. The diversity of antigenic types creates difficulties for prevention of FMD by vaccination because there is no predictable, reproducible and effective protection that can be afforded by a limited number of vaccine antigens against multiple variants cocirculating in different world areas, and sometimes even within the same geographical area (Doel 2003 Sutmoller et al. 2003). Traditionally, vaccine manufacturers have known that it is necessary to tailor vaccine composition to match the antigenic properties of the circulating FMDV in much the same way as the influenza vaccines must be periodically updated. Chemically defined vaccines would be desirable, but they will often fail to provide protection against the diverse and...

Biology of the Viruses

Figure 1 An unrooted phylogenetic tree showing the genetic relatedness between hepadnaviruses isolated from ducks, geese, herons, storks, and cranes. Reproduced from Prassolov A, Hohenberg H, Kalinina T, et al. (2003) New hepatitis B virus of cranes that has an unexpected broad host range. Journal of Virology 77 1964-1976, with permission from American Society for Microbiology.

Genetic Variation and Epidemiology

Figure 2 (a) Organization of the HBV genome. The inner circles depict the complete minus strand and incomplete plus strand and the positions of the direct repeats (DR) are indicated. The blocks surrounding the genome show the locations of the four overlapping ORFs C and S contain two and three in-frame initiation codons, respectively. (b) Organization of the DHBV genome. A simplified view illustrating the single pre-S region and lack of an XORF. (a) Reproduced from Kidd-Ljunggren K, Miyakawa Y, and Kidd AH, etal. (2002) Genetic variability in hepatitis B viruses. Journal of General Virology 83 1267-1280, with permission from Society for General Microbiology. conformational region, comprising a number of overlapping epitopes, is the main target of the humoral response, and antibodies synthesized during convalescence or in response to the hepatitis B vaccine are protective. Two pairs of mutually exclusive subdeterminants, d or y and w or r, correlate with variation (in both cases...

Clinical Features and Pathology

The clinical features of acute viral hepatitis in humans are nonspecific and are not dependent on the etiology of the infection they include fatigue, anorexia, myalgia, and malaise. Jaundice may be evident in the more severe cases, but often the infections may be anicteric (without jaundice) or even asymptomatic. In hepatitis B, these clinical features are evidence of a robust immune response to the virus and a sign that the infection will be cleared by the immune system. In a minority of cases, less than 5 of immune competent adults, asymptomatic infections persist in individuals who do not mount a vigorous immune response. Such persistent infections, originally termed the chronic carrier state, are defined formally by the persistence of HBsAg in serum for more than 6 months. Figure 5 Global prevalence of persistent HBV infection (HBsAg in serum). Reproduced from http www.cdc.gov ncidod diseases hepatitis slideset hep_b slide_9.htm, with permission from Central Food Technological...

Prevention and Treatment of Infection

HBV infection can be prevented by immunization, intramuscular administration of HBsAg leading to a protective anti-HBs response. The first vaccine (so-called plasma-derived vaccine) was produced by purifying HBsAg from the plasma of hepatitis B carriers. Second-generation vaccines contain HBsAg produced from yeast or (less commonly) mammalian cells by recombinant DNA technology. The World Health Organization recommends universal immunization of infants and this is now carried out in many countries. The key is to break the chain of transmission from infected mothers to their infants, and giving the vaccine within 24 h of birth protects 70-90 of such babies. Protective efficacy may be increased by giving passive protection with hepatitis B immune globulin (HBIG) at a contralateral site. In Taiwan, one of the first countries with a high prevalence of HBsAg to introduce universal immunization of infants, that prevalence has been reduced from more than 10 to less than 1 in the immunized...

Virion Structure and Genome Organization

The infectious virion or Dane particle measures about 42 nm in diameter and consists of an outer envelope containing hepatitis B surface proteins (HBsAg) in a lipid bilayer (Figure 2). This in turn encloses the nucleo-capsid core of the virus, within which lies the viral genome and a copy of its polymerase. Apart from virions, liver hepatocytes release into the circulation subviral particles devoid of nucleic acid and consisting entirely of HBsAg. These are the 22 nm spheres and the filamentous The precore core ORF contains two in-frame initiation codons and therefore yields two translation products. Initiation of translation from the first results in synthesis of the precore polypeptide, which forms the precursor of the soluble hepatitis B e antigen (HBeAg). This protein contains a signal peptide at its N-terminus that anchors the protein in the endoplasmic reticulum membrane. Cleavage by signal peptidase in the lumen is followed by further processing of the C-terminus. The resulting...

Structure and Replication of HBV

The 42 nm hepatitis B virion is composed of the DNA genome packaged together with a copy of the virus-encoded polymerase in an icosahedral nucleocapsid made up of dimers of the hepatitis B core antigen, HBcAg. In turn, the nucleocapsid is covered by an envelope composed of a lipid bilayer derived from internal cellular membranes and embedded with the hepatitis B surface protein, HBsAg. The open reading frame (ORF) encoding HBsAg has three in-frame initiation codons (Figure 1) which are used for the translation of the large (L, pre-S1 + pre-S2 + S), middle (M, pre-S2 + S), and small (S or major) surface proteins. All three proteins, which share the same C-terminus, are found in the virions. Figure 1 Organization of the HBV genome. The inner circles depict the complete minus strand and incomplete plus strand, and the positions of the direct repeats (DRs) are indicated. The blocks surrounding the genome show the locations of the four overlapping ORFs C and S contain two and three...

Hepatocellular Carcinoma

Primary liver cancer is among the most common fatal malignancies of humans worldwide. An association with hepatitis B virus (HBV) from the hepadnavirus family was suggested by the geographical coincidence of a high incidence of hepatocellular carcinoma in southeast Asia and equatorial Africa with high rates of chronic HBV infections, generally contracted congenitally. Prospective studies demonstrated about a hundredfold increased risk of hepatoma among carriers of the HBV surface antigen (HBsAg). Integrated HBV DNA can be detected in a large proportion of the tumors from high-risk areas and in hepatoma-derived cell lines. Liver cancer usually develops only after several decades of chronic HBV-induced hepatitis and may thus be triggered by accumulating genetic damage due to inflammation and continuous cell regeneration. A specific contribution of HBV might be expected from cis effects following integration of viral DNA, but except for a few case reports no consistent evidence has been...

Taxonomy and Geographical Distribution

HCV has been classified as the only member of the genus Hepacivirus and grouped together with the genera Pestivirus, Flavivirus, and tentatively the GB-viruses, in the family Flaviviridae. According to phylogenetic analyses, HCV is more closely related to the pestiviruses than to the flaviviruses. Based on genomic heterogeneity, six major genotypes, having more than 30 nucleotide sequence divergence, and more than 70 subtypes differing from each other by 10-30 at the nucleotide sequence level, have been defined. Subtypes are designated by lowercase letters following the number of the genotype (e.g., genotype 1 subtype b 1b). While genotype 1 and 2 viruses are prevalent almost worldwide, HCV genotypes 3-6 are to a large extent restricted to distinct geographical regions, including the Indian subcontinent and Southeast Asia (genotype 3), Africa and Middle East (genotype 4), South Africa (genotype 5), and Southeast Asia (genotype 6). Individual genotypes have not been ascribed to...

Sampling Errors Differential Enrichment and Recovery During Culture

Treponema pallidum PCR for hepatitis C virus In viral load assays conducted to predict the prognosis of patients with HIV and hepatitis C virus, the expense of commercial test kits precludes monitoring with the frequency that might be useful. The sample is a biased one, taken perhaps every 3 months and may not be helpful for showing variations in viral load in the period between samples. As quantitation is the vital aspect of viral load monitoring, factors that alter the number of virions such as delays in transport and processing may lead to errors in assessing this prognostic indicator. Similar considerations apply when sampling shellfish beds for viruses. Representative samples must be taken from the bed to allow for spatial variations, quantity of virus will be affected by the species of shellfish and its filtration rate, and transport and processing should be prompt and temperature controlled.

Virion Properties

HCV particles are enveloped and spherical and have a diameter of 55-60 nm as determined by filtration and electron microscopy (Figure 4). By analogy to other flaviviruses, HCV particles are composed of at least the genomic RNA, the core protein, and the two envelope proteins E1 and E2 which are embedded into the lipid envelope. The core protein forms the internal viral capsid (presumably 30-35 nm in diameter) that shelters the single-stranded RNA genome (Figure 4). The S20W is approximately 200S and infectious HCV virions isolated from the plasma sample of infected patients and chimpanzees have low buoyant densities in the range of 1.05-1.10gml_1.

Tissue Tropism and Host Range

Hepatocytes are considered to be the natural target cells for HCV. Viral RNA was also detected in peripheral blood mononuclear cells (PBMCs) and bone marrow cells but it is unclear whether productive infection occurs in these cells. In cell culture, HCV RNA replication was demonstrated in non-liver cells like human T- and B-cell lines or embryonic kidney cells (293). Furthermore, certain mouse cell lines can support replication of HCV replicons demonstrating that the viral replication machinery is also functional in a murine host cell environment.

Experimental Systems Animal Models

Possibilities to propagate HCV in vivo are rare. For many years HCV could be propagated only in chimpanzees after experimental inoculation with virus containing samples from patients or synthetic in vitro transcripts derived from cloned infectious genomes. More recently, transgenic mice Figure 3 HCV replication cycle. (1) HCV virion binds to one or several receptors on the surface of the cell. Glycosaminoglycans, SR-B1, CD 81, and eventually LDL receptor are required for or contribute to virus binding and entry. (2) The virus particle supposedly enters the cell via clathrin-mediated endocytosis. (3) After a low-pH-mediated fusion step from within an acidic endosome and uncoating, the HCV genome is liberated into the cytoplasm of the host cell. (4) The viral RNA genome is translated at the rough endoplasmic reticulum (rER). (5) The membranous web presumably originating from ER membranes is formed. (6) It is the site of viral RNA amplification which occurs via negative-strand RNA...

Pathogenesis and Tissue Tropism

The pathogenesis of HEV is largely unknown. It is believed that HEV enters the host through the fecal-oral route. However, the primary site of HEV replication is not known. In primates and pigs experimentally infected with human and swine HEVs, virus replication in the liver has been demonstrated. It is believed that, after replication in liver, HEV is released to the gallbladder from hepatocytes and then is excreted in feces. In pigs experimentally infected with human and swine HEVs, in addition to the liver, HEV replication was also identified in extrahepatic tissues including small intestine, colon, hepatic, and mesenteric lymph nodes. Although the clinical and pathological significance of these extrahepatic sites of virus replication is not known, it is believed that HEV may first replicate in the gastrointestinal tract after oral ingestion of the virus, and subsequently spreads to the target organ liver via viremia. It has been well documented that pregnancy increases the...

Humanmediated genetic exchange

In regard to point three, Arnold and Larson (2004) continue, 'Whether transferring delayed ripening genes from a disease of bacteria (i.e. a bacteriophage) into cantaloupe to prevent our breakfast from going mushy too quickly, or splicing a gene for pesticide resistance from bacteria into corn to keep insects from feeding on the plants in a field, or implanting the gene for human interferon into the DNA of chickens so that their eggs contain the protein used to battle hepatitis C, or introducing the gene for a red fluorescent protein from a sea anemone into zebra fish so that they look more attractive to us in an aquarium, biotech researchers now move genes between species so unrelated to

RNA Virus Vector Systems

Poliovirus, a positive-strand RNA virus, has been used to express a number of foreign genes. Poliovirus vectors expressing epitopes derived from hepatitis A virus, rhinovirus 14, human papillomavirus 16, foot-and-mouth disease virus and HIV have been produced. A poliovirus-HIV chimera has been shown to elicit anti-HIV antibodies in rabbits. Furthermore, this antiserum neutralized a wide range of American and African HIV-1 isolates. The major disadvantage of polio, relative to the negative-strand RNA virus vector systems, is that the systems that have been developed thus far have a limited capacity for foreign sequences.

Reading and Interpretation Errors

Misinterpretation of typing may occur and it is important to focus on clinical problem-solving rather than modern methods alone. Typing is not mystical. Its goal is simply to provide evidence that epidemiologically related isolates are also related genetically, represent the same strain, and thus may have a common origin. In larger-scale studies, it may also suggest that genetically related isolates have a common epidemiological source. This may be harder to prove with certainty and gives potential for falsely positive associations that could have costly implications for the agricultural and food industries if food products are mistakenly implicated by overzealous investigators. An outbreak can occur with more than one epidemic strain, and an outbreak is not excluded because of strain heterogeneity (205). Hepatitis C viral quasispecies, heterogenous mixtures of virus particles containing hypervariable regions, sequentially change during the natural course of infection and the...

Atomic Structure of Viral Proteins

There are many functional viral proteins that do not have any symmetrical quaternary structure in virus particles. Therefore, their atomic structure has to be studied by crystallizing isolated proteins. Crystal structures have been determined for the hemagglutinin (HA) and the neuraminidase (NA) of enveloped influenza virus, and the protease and reverse transcriptase of human immunodeficiency virus (HIV) and other retrovirus, matrix and capsid proteins (influenza virus and HIV SIV), a fragment of the HIV glycoprotein gp41, the protease of picorna-viruses, the protease and the thymidine kinase of herpesvirus, the protease of hepatitis C virus, the receptor binding domain of adenovirus fiber and the envelope glycoprotein of tick-borne encephalitis virus.

Diagnosing Wilson Disease A High Index Of Suspicion

Liver biopsy with determination of hepatic copper content is the most valuable single diagnostic procedure. Liver copper > 250 pg g dry weight is highly suggestive for Wilson disease, but may be also found in cholestatic diseases and in idiopathic copper toxicosis. The major shortcoming of a single liver biopsy specimen is underestimation of hepatic copper because of inhomogeneous copper deposition in the liver. Detection of copper in histological specimens by special staining methods such as rhodamine or orcein staining depends on its intracel-lular localization and is therefore insensitive and rarely helpful in establishing diagnosis. The histological findings in Wilson disease may resemble the features of various other liver disorders such as autoimmune hepatitis or nonalcoholic steatohepatitis.

History and General Characteristics

In heavily infected countries or in areas where there is an uncontrollable virus spread, a systematic and strict vaccination scheme should be implemented to curtail virus circulation. Vaccination, however, precludes the use of serology for diagnostic purposes, because the antibody response after vaccination cannot be distinguished from that after infection. Consequently, it is difficult to demonstrate convincingly the absence of HCV which jeopardizes the export of pork. Marker vaccines that allow the differentiation between infected and vaccinated pigs with the use of an epitope-specific serological test will soon become available. These vaccines contain the E2 protein, produced in baculovirus, and are formulated with an adjuvant.