Hepatitis C Virus 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

Alternative Hepatitis C Treatments Summary


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The Hcv Genome And Replication

Hepatitis C does not easily replicate to usable titers in cell culture, a fact that has hindered the study of the molecular biology of this virus. The viral genome is a positive-sense, single-stranded, 9.6-kb RNA molecule with highly conserved 5' and 3' NTR, approximately 341 and 500 nt, respectively, and is encapsidated with a core protein, C, that is enclosed in a membrane containing at least 2 envelope proteins, E1 and E2.150 The 5' NTR is a complex secondary structure, indicating the function of an internal ribosomal entry site,151 whereas the 3' NTR contains a highly conserved 98-nt sequence with a secondary structure which in combination with other sequences and the viral polymerase, NS5B, is necessary for the replication of the minus strand viral RNA.152'153 The genome's single large open reading frame produces a polyprotein that is cotranslationally and post-trans-lationally processed by the combination of host signal peptidases and viral proteinases, resulting in all 11 known...

Evidence For Hcv Involvement In Myocarditis

The literature on HCV involvement in heart disease is not vast and can be divided by results from Japanese and European groups. Matsumori and colleagues160 initially suggested that HCV may play an etiologic role in the development of heart disease. Thirty-six patients with dilated cardiomyopathy were screened for anti-HCV antibodies in serum 16.7 of the patients and 2.5 of controls (n 40) were positive. HCV type II RNA was detectable by RT-PCR analysis in 4 of the 6 patients with antibodies against HCV, and RNA was detected in 3 of the positive patients' heart muscle. Matsumori et al.161 then reported finding serologic evidence of HCV infection in 6 of 35 patients with hypertrophic cardiomyopathy versus 2 to 3 of patients with ischemic heart disease HCV RNA was detected in the heart RNA from 3 of the 6 positive patients who had hypertrophic cardiomyopathy. This was followed by another group's findings that HCV RNA could be detected in the hearts and livers of 3 patients with chronic...

Hepatitis B HBV and C HBC viruses

HBV is a small DNA virus of 3000 base pairs. Primary infection produces either acute hepatitis B or a subclinical infection. The majority of infections resolve with clearance of virus and lifelong immunity 5 fail to clear the virus and go on to develop a lifelong persistent hepatic infection, resulting in a spectrum of hepatocellular injury and the development of chronic persistent hepatitis or chronic active hepatitis. Chronic HBV infection is associated with a 100-fold increase in hepatocellular carcinoma (HCC) risk. Hepatitis C (HCV) is a single-stranded RNA virus and primary infection results in acute hepatitis C infection. HCV infection is linked to the development of HCC.

Hepatitis C Virus RNA

HCV is the major cause of parenterally transmitted non-A, non-B hepatitis (Choo et al., 1989). Until the virus was characterized, diagnosis was made by exclusion of all other known causes of hepatitis. Antibody against HCV is found in over 80 of patients with well-documented non-A, non-B hepatitis. Chronic HCV is characterized by fluctuating alanine aminotransferase (ALT) levels and recognizable changes in liver histology, which may lead to cirrhosis and hepatocellular carcinoma (Alter et al., 1990). Therapy with interferon-a has been approved by the Food and Drug Administration (FDA) and can be effective in eliminating the virus. However, less than half of HCV-infected individuals respond to treatment, and relapse is common (David et al., 1989). A bDNA-amplified test was developed for monitoring the level of the genomic RNA at the conserved 5' untranslated region and a portion of the core gene in individuals infected with HCV. In a study of chronic HCV patients, the bDNA assay...

HCV Genotyping Assays

A variety of laboratory-developed and commercial assays are used for HCV genotyping. The methods include nucleic acid sequencing, reverse hybridization, subtype-specific PCR, DNA fragment length polymorphism, heteroduplex mobility analysis, melting curve analysis and serological genotyping. The FDA has not cleared any of these methods for clinical diagnostic use. A commercially available reverse hybridization line probe assay is the most commonly used method for geno-typing HCV among clinical laboratories participating in the HCV proficiency-testing surveys of the College of American Pathologists. This reverse hybridization assay was developed by Innogenetics to genotype HCV and is now marketed as the Versant HCV Genotype Assay by Bayer. In this line probe assay (LiPA), biotinylated PCR products from the 5' UTR are hybridized under stringent conditions with 19 type- and subtype-specific oligonucleotide probes attached to a nitrocellulose strip. Hybridized PCR products are detected...

Hcv Rna Detection and Quantitation

Detection of HCV RNA in serum or plasma by nucleic acid amplification methods is important for confirming the diagnosis of HCV, distinguishing active from resolved infection, assessing the virologic response to therapy, and screening the blood supply. These tests are incorporated into diagnostic algorithms for HCV proposed by the National Institutes of Health,36 the CDC,37 European Association of the Study of the Liver,38 and National Academy of Clinical Biochemistry.39 The detection of HCV RNA in the plasma or serum is the earliest marker of infection, appearing 1 to 2 weeks after infection and weeks before the appearance of alterations in liver enzyme levels or anti-HCV antibodies. Approximately 80 of individuals infected with HCV will be chronically infected with the virus. In antibody-positive individuals, HCV RNA tests can distinguish active from resolved infections. In patients with a high pretest probability of infection, a positive serological screening test is usually...

Qualitative Detection HCV Assays

There are currently two FDA-cleared qualitative HCV RNA test kits available for diagnostic use, the Amplicor HCV test v2.0 (Roche) and the Versant HCV RNA qualitative test (Bayer). The Amplicor HCV test v2.0 is based on RT-PCR amplification of a portion of the 5' UTR and has an analytical sensitivity of 50IU ml.65 The test incorporates an internal control to detect PCR inhibitors and deoxyuridine triphosphate (dUTP) and uracil-N-glycosylase in the reaction mixture to prevent false positives due to amplicon carryover. The test is available in two formats, a manual microwell plate assay and a semiautomated assay designed for the COBAS instrument. The performance characteristics of the Amplicor HCV tests are well established66 and are the most commonly used qualitative HCV RNA tests in clinical laboratories participating in the proficiency-testing surveys of the College of American Pathologists. The Versant HCV RNA qualitative test also targets the 5' UTR but uses TMA to amplify the...

Hepatitis C Viruses Introduction

Infection by HCV (family Flaviviridae, genus Hepacivirus), the cause of most cases of non-A, non-B viral hepatitis, is a major cause of chronic hepatitis, resulting in liver cirrhosis and hepatocellular carcinoma worldwide146 and infects 175 million people globally. More than 80 of infected patients develop chronic disease while remaining essentially asymptomatic.147 In the United States, an estimated 2 to 3 million people are currently infected and more than 150,000 new cases of HCV infection occur per year. The sequelae of HCV-induced and serious chronic liver disease result in 8,000 to 10,000 deaths annually.147 Since the first report of viral genomic sequences from HCV in 1989, a greater understanding of the HCV infection has been achieved. HCV infection usually develops after direct blood-borne percutaneous exposure. High risk of HCV infection has been reported often after blood transfusion.148 Epidemiologic evidence exists for the transmission of HCV to renal dialysis patients,...

Fatty Liver Hepatitis And Cirrhosis

Chronic alcohol consumption can cause the deposition of excess triglycerol in the liver leading to a condition known as 'fatty liver'. This damage can lead to hepatitis and, if severe enough, to cirrhosis. The damage is thought to be due to the high concentrations of ethanal within the cell and if severe enough will result in cell death. Cell damage and death trigger an inflammatory response, i.e. infiltration of lymphocytes and activation of an immune response. If this is not treated it will lead to the formation of fibrous tissue and a severe reduction in the functioning of the liver.

HCV RNAdependent RNA polymerase NS5B

Ns5b Rna Dependent Polymerase Labelled

Hepatitis C (HCV) virus possesses an RNA-dependent RNA polymerase NS5B, which is essential for viral replication and infectivity.56 NS5B is a Due to detection of dimer-sized, hairpin-like RNA molecules using large heteropolymeric templates derived from the HCV RNA genome, HCV replication was first proposed to go through a fold-back priming mechanism.59,61 However, NS5B has recently been shown to synthesize a full-length HCV genome in vitro in a template-dependent and primer-independent man-ner.62-64 Thus, NS5B does not require a separate primer or a folded-back 3'-template end as a primer. Instead, it recognizes the specific sequences and structures at the 3'-termini of the plus and minus strands of the HCV RNA genome for the initiation of RNA synthesis.62,65 NS5B uses mono-, di-, or trinucleotides efficiently to initiate de novo RNA synthesis.66 Interestingly, it has been shown that a high concentration of rGTP stimulates RNA synthesis by NS5B by up to two orders of magnitude.67 NS5B...

Quantitative HCV Assays

Currently there are several commercially available and proprietary laboratory-developed methods used to quanti-tate HCV RNA levels in patients. The Versant HCV RNA Assay v3.0 (Bayer Corp.),72 which is FDA approved, and the Amplicor HCV Monitor Test v2.0 (Roche Diagnostics)65 are the most widely used commercially available assays. The HCV Superquant is a proprietary RT-PCR assay developed by National Genetics Institute (Los Angeles, CA), which has been used by many investigators in clinical trials of treatment for HCV. The Amplicor HCV Monitor test v2.0 is a quantitative RT-PCR assay that amplifies the same target region as the qualitative Amplicor HCV test. The assay uses an internal quantitation standard to calculate the amount of HCV RNA in a sample. The assay has a sensitivity of 600 IU ml and a 2.9 logi0 dynamic range. Specimens with values greater than the upper limit of quantitation (500,000 IU ml) can be diluted 100-fold and retested as recommended by the manufacturer. The...

Hepatitis B

Serology includes hepatitis B surface antigen as a screening test and hepatitis B core antigen to determine infectivity. There is a 10 carrier rate in South East Asians. Serology should be sent in all high risk patients, e.g. jaundice, IV drug abuse, homosexuals, prostitutes, those with tattoos or unexplained hepatic enzyme abnormalities. In addition, hepatitis B status should be known in staff who suffer accidental exposure to body fluids, e.g. through needlestick injury. Those who are not immune may be treated with immunoglobulin.


Hepatitis can be acute and short in duration or chronic and long-lasting. Liver cells are either inflamed and damaged or they die, leaving a malfunctioning liver. Viruses are the most common cause of hepatitis, indicated by alphabetical letters other causes are alcohol, exposure to industrial chemicals, fumes, and drugs, recreational or pharmaceutical, including acetaminophens like Tylenol. Symptoms include fatigue, fever, nausea, vomiting, loss of appetite, and possibly dark urine and a yellowing of the skin called jaundice. Hepatitis A can be transmitted by poor hygiene and through food. Hepatitis B and C are transmitted by sexual contact and blood.

Hepatitis A

Diagnosis Hepatitis A. -Hepatitis A immune globulin, 0.02 mL kg IM (usually requires multiple injections at different sites), when given within 2 weeks after exposure to HAV, is 85 effective in preventing symptomatic infection. -Hepatitis A vaccine (Havrix) if 2 years 0.5 mL IM,

Hepatitis B Virus

Hepatitis B core antigen DNA, immobilized on nylon membrane, is hybridized with an alkaline phosphatase-labeled oligonucleotide probe. Hybridized probe is then detected with the 1,2-dioxetane substrate AMPPD (Bronstein et al., 1989c). Hepatitis B core antigen plasmid DNA and alkaline phosphatase-labeled probe, included in a SNAP Hybridization System, and GeneScreen Plus nylon membrane were obtained from NEN DuPont (Boston, MA). AMPPD and CSPD are from Tropix. Figure 2 Chemiluminescent detection of hepatitis B core antigen plasmid DNA with AMPPD substrate in alkaline phosphatase-based DNA hybridization assay. Reprinted with permission from Bronstein et al. (1989c). Figure 3 Hepatitis B virus core antigen plasmid DNA hybridization assay. Reflection density vs. number of copies of target DNA. Densitometrie analysis of the Polaroid instant black and white photographic film image 0.00 (white)-2.00 (black) . Reprinted with permission from Bronstein et al. (1989c). Figure 3 Hepatitis B virus...

HCV Genotypes

The first complete HCV genome sequence was reported by Choo et al. in 1991.24 As additional genome sequences from isolates from different parts of the world were determined and compared, it was evident that HCV exists as distinct genotypes with as much as 35 sequence diversity over the whole viral genome.25 Much of the early literature on geno-typing is confusing because investigators developed and used their own classification schemes. However, a consensus nomenclature system was developed in 1994. In this system the genotypes are numbered using Arabic numer- Table 37-3. Terms Describing Genomic Heterogeneity of HCV Source Adapted from Zein NN. Clinical significance of hepatitis als in order of their discovery, and the more closely related strains within some types are designated as subtypes with lowercase letters. The complex of genetic variants found within an individual isolate is termed the quasispecies. The quasispecies result from the accumulation of mutations that occur during...

HCV Genotyping

Sequence analysis of variable regions of the HCV genome has been used to investigate outbreaks of infection and to study modes of transmission. Two large outbreaks of infection associated with contaminated lots of anti-rhesus D immunoglobulin (anti-D) in Ireland and Germany were investigated using molecular typing.54,55 In both studies, sequence analysis showed that the virus infecting the women was the same as that found in the implicated batches of anti-D. In another report, sequencing part of the NS3 region provided evidence of patient-to-patient transmission during colonoscopy.56 Sequence analysis also is becoming a routine part of investigations of HCV infections associated with blood transfusions. In addition, molecular analysis has been used to study vertical and sexual transmission of HCV.57-60 Although a number of baseline factors are predictive of response to treatment of chronic hepatitis C infection, HCV genotype is the strongest and most consistent predictor for achieving...

Hepatitis C

What Anti Hcv Means

Chronic hepatitis C occurs only infrequently in childhood. Based on our own research, the estimated rate is about 1 2000 children in Germany 13 . Many of these patients were found to have received blood or blood prod- Table 2. Advantages and disadvantages of antiviral medications for chronic hepatitis B Table 2. Advantages and disadvantages of antiviral medications for chronic hepatitis B ucts, in other words a treatment via parenteral injection in countries where inadequate measures of sterilization were practiced. While this method of infection is becoming increasingly less important, the vertical route of infection for HCV is steadily increasing. Screening tests to determine the levels of anti-HCV antibodies are conducted using commercial tests, whereas HCV-RNA is detected via PCR. Usually a PCR is conducted to quantify the viral-load , which provides the number of circulating HCV genomes. A positive finding is followed by HCV geno-typing. Characteristically, the transaminases...

Specimen Processing

Specimen storage time and temperatures can have a significant impact on nucleic acid recovery and the efficiency of subsequent diagnostic procedures. Lysis of red blood cells can influence PCR reactions by inhibition of Taq DNA polymerase by heme. Heme can also bind to and damage DNA at the elevated temperatures used in PCR reactions (Winberg, 1991). In addition, lysis of granulocytes releases proteases and nucleases that degrade viral particles and nucleic acids. Cuypers et al. (1992) reported a 1000- to 10,000fold reduction in hepatitis C virus (HCV) RNA concentrations when whole blood and serum were stored at room temperature. However, degradation was even faster when whole blood was stored at 4 C, presumably because of increased granulocyte lysis at 4 C relative to room temperature. The recommended method for storing specimens for HCV testing is allowing the blood to clot, removing the serum, and storing the serum at 4 C or -20 C.

Microorganisms Of Concern

Harris et al. 8 extensively reviewed outbreaks associated with fresh produce and reported that the most common human pathogens associated with produce foodborne illness outbreaks are E. coli O157 H7, Salmonella spp., Shigella spp., Listeria monocytogenes, Crytosporidium spp. 9 , Cyclospora spp., Clostridium botulinum, hepatitis A virus, Norwalk virus, and Norwalk-like viruses. These microorganisms can be categorized as follows Pathogenic viruses (hepatitis A, enterovirus, Norwalk-like viruses). Data from the CDC foodborne outbreak surveillance system show that from 1988 to 1998 the two most commonly reported microorganisms associated with fresh produce foodborne illness outbreaks were Salmonella spp. and E. coli O157 H7 with 45 and 38 of the fruit and vegetable linked outbreaks, respectively, being attributed to these two microorganisms. However, recent foodborne illness outbreaks associated with produce consumption have been caused by viruses (hepatitis A) and parasites (Cyclospora...

Prevention of Transmission of Human Immunodeficiency Virus and Other Blood Borne Pathogens in Health Care Settings

Only blood, semen, vaginal secretions, and possibly breast milk have been implicated in transmission of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and other blood-borne pathogens. (Adapted from Centers for Disease Control Recommendations for prevention of HIV transmission in health care settings. MMWR 36 Suppl. 25 1987. Centers for Disease Control Update Universal precautions for prevention or transmission of human immunodeficiency virus, hepatitis B virus, and other blood-borne pathogens in healthcare settings. MMWR 37 24, 1988)

Pyrimidine Antagonists

Meta-analysis of several randomized trials comparing various 5-FU schedules of administration has shown the superiority of continuous infusion of 5-FU over bolus administration when given as a single agent.87 Moreover, bolus drug administration cannot achieve effective radiosensitization, as this requires constant drug exposure given the short half-life of 5-FU. Clinical toxicities also have some correlation with schedule of administration. Myelosuppression, especially leukopenia, is more pronounced with IV bolus schedules than with continuous infusion. Mucositis along the GI tract can be debilitating and dose limiting, especially with continuous infusion. Other GI symptoms, such as nausea, vomiting, and anorexia, can also be more severe with continuous infusion. With HAI regimens, systemic toxicities of 5-FU are dose limiting whereas hepatitis is usually mild. On the other hand, local-regional toxicities such as gastritis, gastric ulcers, enteritis, hepatitis, cholestasis, or...

The Organ Procurement Process

The coordinators also are responsible for ordering laboratory tests to determine the presence of any transmissible diseases such as HIV, hepatitis or other systemic infections. All OPOs have Medical Directors or physicians designated to oversee and assist as necessary in the screening and medical management of donors. Their level of involvement in a given case depends on the complexity of the case and the experience level of the coordinator. Additionally, physicians from each of the receiving transplant teams may request specific tests or management parameters. It is the role of the coordinator of the host OPO to coordinate the

Initiatives To Increase Donation

One fairly successful approach to increasing the organ supply has been to broaden the criteria for donor acceptance, but only to the extent that donation can occur without negatively impacting transplant outcomes. As transplantation technology has evolved, transplant physicians have discovered that donor organs that had previously been considered unacceptable are often quite suitable for transplantation. It is not surprising that as donor management and post-transplant care of the recipient have improved, so has the ability to use organs from expanded donors a term coined by transplant professionals in the mid 1990s. There are many examples of expanded donors, and undoubtedly the list will continue to grow. Acceptance of organs from older donors, donors with some degree of hypertension, non-heartbeating donors, Hepatitis C positive donors, and other expanded donors all have been used effectively given the appropriate donor patient circumstances. Some disagreement remains regarding...

Evaluation And Selection Of Donors

Obtaining consent for organ donation is of paramount importance in increasing organ donation. A caring sensitive approach by trained individuals that have time to spend with families cannot be overstated. Organ procurement personnel, clergy, and nursing staff play a vital role in this area. Once consent is obtained, a review of the patient's history should focus on the mechanism of death, periods of hypotension or cardiac arrest, need for vasoactive medications, and previous surgery. Likewise, the patient's social history, including alcohol and drug use, should be known. Generalized infectious diseases are ruled out by obtaining human immunodeficiency virus (HIV) antigen, anti-HIV-1, anti-HIV-2, human T-cell lymphotoxic virus (HTLV)-1 and HTLV-2, anti-cytomegalovirus (CMV), antihepatitis C virus (HCV), hepatitis B surface antigen (HBSAg) and hepatitis B core antibody. Specific organ function is primarily determined by laboratory data, chest x-ray, electrocardiogram, and...

The Art And Science Of Diagnosis

Quired before diagnostic examination or clinical treatment is undertaken. Some patients require antibiotic prophylaxis before clinical examination because of systemic conditions like heart valve replacement, a history of rheumatic fever, or advanced AIDS. Patients who daily take anticoagulant medications may need to have the dose reduced or dosing suspended if the clinician is to conduct the thorough periodontal examination, which is integral to a complete endodontic workup. When patients report being infected with communicable diseases such as AIDS, hepatitis B, or tuberculosis, dentist and staff need to be especially attentive to the use of protective barriers. In case endodontic therapy is required, the clinician must know what drugs the patient is taking so that adverse drug interactions can be avoided. In such cases, consultation with (he patient's physician is recommended. Patients who present with mental or emotional disorders are not uncommon. Some patients are aware of their...

The Application Of Molecular Forensics And Epidemiology To Viral Infections

The tracking of HIV infections provides excellent examples of the successful application of molecular forensics to identify the source of a viral infection. In 1990, an HIV-positive dentist in Florida was suspected to be the source of HIV infection in six patients with no known risk factors. The sequencing of the env gene from viruses isolated from the doctor and patients strongly corroborated the epidemiological data that suggested the transmission route.1 In more recent cases, polymerase chain reaction (PCR) amplification of the HIV genes followed by phylogenetic analyses have been used to suggest HIV transmission from a surgeon to a patient2 and from a nurse to a patient.3 Molecular forensics has been applied to other viral infections in addition to HIV The nosocomial spread of specific strains of hepatitis C virus infections in hemodialysis units, for example, has been documented in several instances.4,5

Reverse Transcription Polymerase Chain Reaction

Reverse transcription-polymerase chain reaction (RT-PCR) may be thought of as RNA-based PCR. RT-PCR was made possible by the discovery in the early 1970s of retroviral reverse transcriptase (RT), an RNA-dependent DNA polymerase, by David Baltimore and Howard Temin,27 for which they shared the Nobel Prize in 1975. Reverse transcriptase catalyzes DNA synthesis using RNA as the template, producing a DNA strand complementary to the RNA template, called complementary DNA (cDNA). Because cDNA is not subject to RNase degradation, it is far more stable than the corresponding RNA. Complementary DNA can be treated like any other DNA target in subsequent PCR. Logistically, RT-PCR is trivially more time-consuming than PCR due to the extra enzymatic step of reverse transcription, but there are enzymes that combine reverse transcription and DNA polymerase activities, making RT-PCR more efficient. With the introduction of techniques to successfully isolate and protect RNA from ubiquitous RNases, and...

Evidence Linking Diet To Cancer

Chapter 1 describes the worldwide epidemiology of cancer. The estimated incidence rates for various cancers worldwide in 2002 found lung, colon rectum, and stomach to be the most common cancers in both men and women, as well as prostate and liver cancer in men, and breast and cervical cancer in women.3 The pattern of cancer distribution based on incidence and mortality rates varies geographically. In general, the predominant cancers in economically developing countries contrast to those in the industrially developed world. For Asia, Africa, and Latin America, there is a relatively high rate of cancer of the upper aerodi-gestive tract, stomach, liver, and cervix, whereas in Europe and North America there is a relatively high rate of cancer of the colon rectum, breast, and prostate. These Western cancers have a strong environmental component, with diet and lifestyle factors particularly important, while in developing countries, infections with such agents as viral hepatitis and...

Expert Committee On The Definition Of Viral Cardiomyopathy

Because isolation of the virus from swabs or tissue is possible in only the acute phase of infection, it is unlikely to succeed in patients with longer-lasting diseases or chronic infections. Enteroviruses, therefore, have been isolated effectively in pediatric patients only. A higher sensitivity is achieved with molecular techniques (eg, gene amplification), which are significantly more sensitive than standard histochemical techniques for the detection of viral proteins. Except for human immunodeficiency virus, hepatitis C, and cytomegalovirus, serologic assessment of antiviral antibodies appeared to be of limited diagnostic value with respect to the actual disease status of the patients and for the critical issue of whether the viral genome is present in the myocardium. The highest sensitivity and reproducibility for the detection of enteroviral genomes were achieved with frozen tissue (100 ) in 5 of 9 centers. Reverse transcription (RT) PCR of enterovirus RNA from fixed embedded...

Introduction To Viral Kinetics And Outcome

Periods may be caused by chronic infections. For example, rabies virus may remain silent for 30-100 days after an animal bite before causing sudden disease demanding medical treatment. Other stealth viruses, such as HIV, hepatitis B and C, and papilloma viruses, may bring about a mild ailment initially that may gradually progress to a fatal disease. Patients with chronic infections may seroconvert and have detectable virus even in the presence of antibodies. Others may be persistently infected by a virus, yet never develop symptoms. These carriers may have low levels of virus, which could potentially be transmitted to other individuals despite being below the level of assay detection. An understanding of how the host responds to viral infection aids investigators and health care workers in identifying and treating infection.

The Role Of The Immune System In Type B Adverse Drug Reactions

Less well understood are the immunological mechanisms that underlie severe skin reactions such as Stevens-Johnson syndrome and immunoallergic hepatitis. There is clear chemical evidence from in vitro studies that the drugs associated with these reactions can undergo oxidative metabolism to chemically reactive metabolites that can haptenate proteins (Park et al., 1995). In addition, both humoral and cell-mediated responses directed against drug-induced antigen have been detected in patients, for example in halothane hepatitis (Pohl et al., 1990). With some compounds the immune response seems to be directed predominantly towards an autoantigen. For example, in tienilic acid-induced hepatitis, patients have circulating autoantibodies directed against the P450 isoform (CYP2C9), which is responsible for the bioactiva-tion of tienilic acid (Beaune and Bourdi, 1993).

Trxtransgenic Mouse

There are several reports showing that TRX-Tg mice are resistant in several disease models. Using the brain infarction model, TRX transgene expression in mice reduced the focal ischemic injury after the middle cerebral artery occlusion with the decreased production of oxidized proteins (54). In the renal warm ischemia-reperfusion model, TRX-Tg mice show the resistance to the damage in the vulnerable thick ascending limb in the outer medulla of the kidney (57). Thioredoxin-transgenic mice are resistant to the bleomycin-induced lung injury (58), the adriamycin-induced cardiotoxi-city (59), or the retinal photo-oxidative damage induced by the intense white fluorescent light (60). Moreover, overex-pressed TRX attenuated the acute lethal hepatitis induced by drugs, such as thioacetamide or lipopolysaccharide (LPS) plus D-galactosamine, suggesting that TRX protects mainly mitochondria-mediated apoptosis (61).

The routes and risks of addiction

The route of use also affects risk, most notably with the risk of infection from intravenous use, especially when needles are not cleaned or are shared. The majority of current intravenous users are hepatitis C positive and we can therefore expect cirrhosis to become a major cause of their death in the next decade or so. This also raises ethical and economic issues interferon treatment significantly reduces the progression of the disease but is costly and its routine use in addicts would be massively expensive and likely to cause public disquiet. The other main infections are hepatitis B and AIDS. The frightening rise of AIDS in drug abusers, where it occurred faster than in any other group, was the main impetus to the harm-reduction approach becoming the treatment style of the 1990s. Needle-exchange programmes and increased methadone availability were both proven to reduce the spread of AIDS and have become the cornerstone of treatment in many countries.

Systemic nonhepatic infection and bacteremia

Hepatic involvement as just one component of a more generalized systemic infection occurs with some viruses (cytomegalovirus, Epstein-Barr virus), protozoa (Coxiella), parasites (malaria), and fungi (hepatosplenic candidiasis), particularly in immunosuppressed patients. Typhoid fever may cause an unusual hepatitis, but the jaundice in leptospirosis is due to hemolysis rather than hepatocellular injury.

Who uses drugs and why

Only 3 per cent of the drug-using population ever injects, but those who do expose themselves to greatly increased risks of accidental overdose, poisoning by adulterants and impurities, and life-threatening infections. Superficial veins progressively thrombose, necessitating recourse to the larger vessels in the neck or groin where damage to an adjacent artery or nerve may threaten life or limb. A sizeable minority persist in exposing themselves to the risk of hepatitis and HIV through the sharing of equipment, and this is particularly prevalent among younger injectors.

What is meant by the harmreduction approach

Whether through success of this strategy or just good fortune, a serious HIV epidemic among injectors similar to that experienced in the United States and some European countries has not materialized in the United Kingdom. Unfortunately, the same cannot be said about hepatitis C, which is becoming rampant.

The range of service providers and the impact of treatment

Those who experience problems with opiates may present to wide range of professionals within the health-care, social, and legal systems. The range of treatment options available within statutory and non-statutory agencies will vary, as will the provision of either maintenance or detoxification for opiate dependents depending upon differing treatment philosophies and treatment settings. Partly in response to this diversity of resource provision, an ongoing multicentre prospective outcome study (National Treatment Outcome Research Study) was set up in 1995 to compare the impact of different treatment approaches on subsequent drug use as well as upon psychosocial and physical outcomes. Preliminary results2** suggested that all four types of intervention (residential rehabilitation, inpatient drug dependency units, methadone maintenance, and reduction) led to reductions in illicit drug use and criminal activity as well as reductions in injecting and sharing behaviours. Least impact was...

Transplantation and other treatment options

Transplantation remains the treatment of choice for a subgroup of patients with a poor prognosis. A variety of models have been developed, including assessment of liver volume (volumes below 700 cm3 resulting in transplantation), assessment of percentage necrosis on biopsy (complicated by sampling error), and a variety of prognostic models. These need to be simple to apply in the clinical setting and to achieve a high level of sensitivity and specificity in discriminating survivors and non-survivors. Two models are commonly used in Europe. In the first, criteria for poor outcome in non-acetaminophen-induced liver failure have been established as the findings of coma or confusion in association with a factor V level below 20 per cent of normal in patients less than 30 years of age, or below 30 per cent of normal in those aged 30 years or above. In the second, the criteria separate acetaminophen and non-acetaminophen patients. For acetaminophen, the criteria are an arterial pH below 7.3...

The drug user with comorbidity

Drug users may also be at risk of physical comorbidity because of their administration of drugs via injection, where they use infected needles syringes or an unsafe injecting procedure. These risks include septicaemia, inadvertent overdose, and risks of infection with HIV, hepatitis B and C, and other blood-borne viruses (see above). The nature of this comorbidity may be causal, consequent, or coincidental and will include psychiatric as well as physical comorbidities.

Nk Cells In Therapy Of Cancer

Among the best-known activators of NK cells are IL-2 and IFNa 28,73 , These two cytokines have been used extensively not only for patients with malignancies but also for those with viral infections. For example, IFNa has been therapeutically effective in a proportion of patients with chronic hepatitis B infection 74 , and patients with human immunodeficiency virus have received systemic IL-2 therapy in combination with zidovudine 75 , For patients with advanced malignancies unresponsive to other treatments, both IL-2 and IFNa therapies have resulted in a low frequency of durable responses 76,77 , Systemic or locoregional therapy with IL-2, even at low or moderate doses, leads to well-documented increases in the number of circulating NK cells and NK activity 78 , Although the extent of this IL-2-induced stimulation of NK activity in vivo could not be directly linked to clinical response, it may be at least partly responsible for the antitumour effectiveness of cytokine-based...

Advanced Concepts

The Western blot method is used to confirm enzyme-linked immunoassay results for human immunodeficiency virus (HIV) and hepatitis C virus among other organisms. In this procedure, known HIV proteins are separated by electrophoresis and transferred and bound to a nitrocellulose membrane. The patient's serum is overlaid on the membrane, and antibodies with specificity to HIV proteins bind to their corresponding protein. Unbound patient antibodies are washed off, and binding of antibodies is detected by adding a labeled antihuman immunoglobulin antibody. If HIV antibodies are present in the patient's serum, they can be detected with antihuman antibody probes appearing as a dark band on the blot corresponding to the specific HIV protein to which the antibody is specific.

From Research to Administration

Although Michael Bishop and Harold Varmus still worked together from time to time, Varmus had his own laboratory at UCSF after 1984. He remained at the university until 1993, doing research on oncogenes and on viruses such as the hepatitis B virus, which causes a serious liver disease.

Equipment Required for Fusion and Growth of Hybridomas

The use of biohazard hoods should be regarded as mandatory for any tissue culture work using human cells or any other material of human origin. As a general rule, the use of hypodermic needles should be avoided when using human material, and great care must be taken to guard against infection with hepatitis or human immunodeficiency viruses.

Criteria for organ donation

In all cases brain death must have been established and the consent of the next of kin and, where appropriate, the coroner must have been obtained. Blood samples should be obtained for screening for hepatitis and HIV, as well as blood group determination and tissue typing. The organs must be removed by a surgeon who has examined the donor and is satisfied with the diagnosis of brainstem death. The procedure must be performed under full operating conditions in theater. If there is any doubt, the local transplant co-ordinator should be contacted early for advice on donor individual organ suitability.

Clinical Evidence Of Enteroviral Infection In Cardiomyopathy

Viral infection has been clearly associated with acute episodes of myocarditis in which a patient often presents with cardiomyopathy and heart failure. Many different infectious agents have been considered as the cause of viral myocarditis, including enteroviruses, adenovirus, cytomegalovirus,3'4 hepatitis C virus,5 and others. Among the most commonly identified infectious agents are the CVBs, members of the enterovirus genus of the picornavirus family. Reports of isolation of coxsackievirus from the heart or pericardial fluid of patients with acute myocarditis date back as far as 1965,6J with numerous reports since of virus isolated from the heart or pericardial fluid or demonstrating the presence of viral antigens in diseased heart tissue.7-14 According to World Health Organization surveys from many different countries, 34.6 per 1,000 of all CVB infections are associated with cardiovascular disease.15

Was the substance truly blood Was it the patients blood

Variceal bleeding is rare in infancy, although gastroesophageal varices associated with portal hypertension are the most common cause of significant GI bleeding in older children. Gastroesophageal varices form in children with intrahepatic or extrahepatic causes of portal hypertension rarely in association with congenital heart disease or vascular malformations. Portal vein thrombosis is a common cause of extrahepatic obstruction. Risk factors include omphalitis, history of umbilical vein cannula-tion, and dehydration. Intrahepatic portal hypertension is caused by hepatic parenchymal disorders. More common associated diagnoses include biliary cirrhosis with biliary atresia, hepatitis, congenital hepatic fibrosis, ( -antitrypsin deficiency, and cystic fibrosis.

Finding new medicines for flaviviral targets

With the incidence of dengue fever increasing all over the world, there is an urgent need for therapies. While drug discovery for any disease is a long and difficult process with uncertain success, dengue fever poses an additional complication in that most of the target patient population is young and lives in developing countries with very limited health care budgets. Recent progress in drug discovery for dengue and an analysis of approaches toward hepatitis C virus (HCV) therapeutics suggest that NS5 polymerase is the most promising target for dengue. Moreover such inhibitors may be useful for several other flaviviral diseases. NS3 proteases will be more challenging targets, especially if oral delivery is desired. Recent work has shown that potent inhibitors can be designed readily, but optimization of pharmacokinetic parameters will probably be a long an arduous task, especially since the primary binding pockets prefer to bind basic amino acids. NS3 helicase can also be...

Spontaneous Methods Used At The Case Series Characterization Step

Within the reported case series, different clinical outcomes may be associated with different age groups, gender, dosage, or concomitant medications (Inman et al., 1970 Bateman et al., 1986 Amery, 1994). Halothane-hepatitis is a classic example of the sometimes substantial impact such numerator-only (internal correlative) characterizations can have (Inman and Mushin, 1974). In this instance, a product-AE case series demonstrated a decreasing time-to-onset with increasing numbers of exposures, thereby supporting an associative argument and providing a potential explanatory mechanism (allergy) by which the event could occur. Numerator only'' characterizations are also the basis for many spontaneous registries (e.g. disease or pregnancy outcomes) where the primary interest lies in patterns of relevant features among the cases.

Pattern Of Mosaic Attenuation

Figure 15 Pneumocystis carinii pneumonia. HRCT of a 56-year-old woman on steroid therapy for autoimmune hepatitis shows characteristic patchy areas of ground-glass opacification. Figure 15 Pneumocystis carinii pneumonia. HRCT of a 56-year-old woman on steroid therapy for autoimmune hepatitis shows characteristic patchy areas of ground-glass opacification.

Minor group antigens also may uncommonly contribute to

Hemolytic anemias, transfusions, and trauma associated with hematomas result in increased bilirubin load and are causes of indirect hyperbilirubinemia in any age group. Infants with galactosemia and hypothyroidism may present initially with indirect hyperbilirubinemia in the newborn period. Congenital infections (eg, cytomegalovirus, toxoplasmosis) that cause systemic illness may be associated with hemolysis and indirect hyperbilirubinemia, in addition to hepatitis and direct hyperbiliru-binemia. Indirect hyperbilirubinemia may be exaggerated in the presence of the following risk factors Asian or Native American race, prematurity, polycythemia, male sex, Down syndrome, oxytocin induction, delayed stooling, and having a sibling with a history of neonatal jaundice.

Prevention And Treatment

A vaccine is a solution that contains a harmless version of a virus, bacterium, or a toxin that causes an immune response when introduced to the body. Vaccination is a highly effective way to prevent viral infection. Viral vaccines can be made from inactivated viruses, attenuated viruses, or parts of the viral coat. An inactivated virus is not able to replicate in a host. An attenuated virus is a weakened form of the virus that cannot cause disease. In general, attenuated viruses provide greater protection from disease. Vaccines against measles, mumps, rubella, polio, hepatitis A and B, and chickenpox have greatly reduced the incidence of these diseases. The genetic diversity of HIV makes the development of an AIDS vaccine a difficult task. Educating people about HIV transmission is currently the best approach to slowing the spread of AIDS. Researchers have used the tools of molecular genetics to search the waters around many coastal cities for viruses known to cause human disease....

Complexes of Acyclic Nucleotide Analogs

One way to alter the cyclic ribose residue of a nucleotide is to 'delete' it. Indeed, acyclic nucleotide phosphonates, i.e., analogs of (2'-deoxy)nucleoside 5'-mono-phosphates, have been increasingly studied during the past two decades. One of these compounds, 9- 2-(phosphonomethoxy)ethyl adenine (PMEA Adefovir see Figure 12, bottom, right) was approved in 2002 2003 in the form of its bis(pivaloyl-oxymethyl)ester for use in the therapy of hepatitis B, a disease evoked by a DNA virus. Diphosphorylated PMEA2-, i.e., PMEApp 4-, is initially recognized by nucleic acid polymerases as an excellent substrate, but after insertion into the growing nucleic acid chain, transcription is terminated due to the lack of a 3'-hydroxyl group. Based on the metal-ion-binding properties of PMEApp 4- it can be explained why the ether oxygen in the aliphatic chain, R-CH2-O-CH2-PO3pp 4-, is compulsory

Venoocclusive disease

Presents clinically early post-transplant (usually within the first 14d). Pathophysiology poorly understood. Risk factors for severe VOD include intensive conditioning regimens, pre-transplant hepatitis and second transplants. VOD is characterised by a triad of hepatomegaly, jaundice and ascites (resulting in rapid post-transplant weight gain) as a result of this. Commoner in allografts than autografts.

Detection Of Viral Genomes In The Heart By Rtpcr

In the last decade, another highly sensitive technique, the PCR, has become the most commonly used method for the detection of viral DNA and RNA sequences in the heart of patients with myocarditis and DCM. Primarily as a result of the identification of different viral nucleic acids in the myocardium of these patients by PCR, it is widely thought that myocarditis can develop as a result of infection with enteroviruses,4 adenoviruses,5'6 cytomegalovirus,6'9 Epstein-Barr virus,12 herpes simplex virus,6 human herpesvirus-6,13 HIV,14 influenza A and influenza B virus,18 PVB19,15-17 or hepatitis C virus.21,22 Martin et al.5 reported in a PCR analysis of children with acute myocarditis that viral sequences were present in 26 of 38 myocardial samples (68 ) 8 enterovirus, 15 adenovirus, 2 herpes simplex virus, and 1 cytomegalovirus. In addition, PCR analysis of endomyocardial biopsy specimens suggests that fibroelastosis is a sequela of viral myocarditis after infection with mumps virus ( 70...

Acquired neutropenias

A mild self-limiting reduction in absolute neutrophil count is most commonly seen following an acute influenza infection. Neutropenia develops during the acute viremic phase of the infection and can persist for up to a week without serious sequelae. Concomitant diminution of other cell lines is unusual in this setting, and diagnosis is aided by a history of an influenza-like illness and reactive lymphocytes with toxic granulation of the neutrophils on the blood film. Protracted neutropenia can occasionally occur with viral hepatitis, Kawasaki disease, and infectious mononucleosis. The mechanism of neutropenia is unclear but probably results from direct suppression of myelopoiesis and increased utilization of neutrophils.

Treatment of nonbacterial infections

Cytomegalovirus is an important opportunistic pathogen following organ transplantation. It is associated with a variety of clinical syndromes including pneumonitis, colitis, hepatitis, mononucleosis, retinitis, and encephalitis. In bone marrow transplant patients, the risk of cytomegalovirus pneumonitis is further increased in patients with graft versus host disease. Mortality from cytomegalovirus infections is high, particularly in patients with pneumonitis. Two agents, ganciclovir and foscarnet, are currently available for the treatment of cytomegalovirus. Major side-effects of these drugs include bone marrow and renal toxicity.

The Hepatic Microvascular System

The portal blood represents a route through which infectious gut-derived organisms can enter the liver. Specific mechanisms have evolved to instigate and regulate inflammatory responses against invading pathogens. The close proximity and cross-talk between the different cells within the liver dictates that many of the hepatic cells are involved in an inflammatory response. Unfortunately the development of an inflammatory response, if uncontrolled, can manifest in permanent liver injury. Indeed, there is irrefutable evidence for the involvement of inflammatory cells in a large number of known liver diseases, including alcoholic hepatitis and cirrhosis, viral hepatitis, ischemia-reperfusion injury (transplantation, tumor resection, shock), sepsis- or endotoxin-induced liver injury, acute and chronic rejection, primary biliary cirrhosis, and primary sclerosing cholangi-tis. Following is an overview of the inflammatory cells, molecules and mechanisms used by the liver to combat and...

Pharmacovigilance And Product Liability

The circumstances in which a medicinal product may be rendered defective by reason of information acquired through pharmacovigilance have yet to be explored fully in any reported cases under Part 1 of the UK 1987 Act of which there are currently fewer than 10. Across the EU, there is a general paucity of reported cases under the national legislation implementing the Directive. The provisions of the Directive were, however, reviewed in depth by the English High Court in the Hepatitis C case (A and others v. The National Blood Authority and others 2001 All ER (D) 298 (MAR)), in which 114 claimants sought damages under the 1987 Act after being infected with Hepatitis C virus through blood transfusions. Mr Justice Burton held that the unavoidability of the harmful characteristic of the product was irrelevant to whether it was defective. He also held that the medical profession's knowledge of the risk of infection, which was not shared by the public at large, did not assist the Defendants....

Artificial Dna Putting Together The Pieces

PCR and DNA probes have been of great value to the areas of molecular biology, medicine, and biotechnology. Using these tools, scientists can detect the DNA associated with HIV (the virus that causes AIDS), Lyme disease, chlamy-dia, tuberculosis, hepatitis, HPV (human papilloma virus), cystic fibrosis, muscular distrophy, and Huntington's disease.

Alcohol Dependence Sleep and Immunity

In addition to poor sleep, alcohol dependent patients are also more prone to infectious diseases such as pneumonia (Nelson and Kolls 2002), tuberculosis (Buskin, Gale, Weiss, and Nolan 1994), hepatitis C (Balasekaran et al. 1999) and possibly HIV infection (Crum, Galai, Cohn, Celentano, and Vlahov 1996), suggesting broad impairments in host defense.

Haemophilia management

General regular medical and haemophilia review and lifelong support are essential. At presentation establish blood group, liver function and baseline viral status (HIV, HCV, HBV, HAV). Vaccinate against HBV and HAV if not immune. Regularly check inhibitor status, LFTs, FBC. Avoid aspirin, anti-platelet drugs, and IM injections. Early treatment of bleeding episodes is essential. Prophylaxis is preferable to demand treatment for many patients with severe haemophilia. Prophylaxis started in first year or two of life can prevent most if not all joint damage and almost eliminate signif

Industrial Application Show Me The Money

Industrial applications of recombinant DNA technology include manufacturing protein products by the use of bacteria, fungi, and cultured mammal cells. The pharmaceutical industry is producing several medically important polypeptides using biotechnology. An example is bacteria that metabolize petroleum and other toxic materials. These bacteria are constructed by assembling catabolic genes on a single plasmid and then transforming the appropriate organism. Another example is vaccines. The hepatitis B vaccine is made up of viral protein manufactured by yeast cells, which have been recombined with viral particles.

Inadequate Sleep and Disease

The correlation between life expectancy and time of sleep has been demonstrated by some (Pollack, Perlick, Linsner, Wenston, and Hsieh 1990 Kripke, Simons, Garfinkel, and Hammond 1979), but not all authors (Wingard and Berkman, 1983 Nilsson, Hedblad, and Berglund 2001). Two recent studies are noteworthy mentioning and deserve to be divulged due to their importance for public health and because of the growing amount of people working at night or whose sleep is seriously impaired. The first study reveals that partial sleep deprivation following immunization against hepatitis A reduces the production of antibody titers, in addition to changes in hormones secretion, including prolactin and cortisol (Lange et al. 2003). The second study reports that, compared to individuals who sleep, partially sleep-deprived individuals also exhibit impairment of antibody production against Influenza virus. The antibody titers were determined in the fourth week postimmunization, at a time when production...

Mantelhaenszel Chisquare

As an example, suppose we want to examine the relationship between hepatitis B and the punker practice of inserting safety pins in earlobes and noses. Because other practices in this subculture, such as using injectable drugs, might also lead to a higher rate of hepatitis, we may wish to stratify by drug use none, moderate, and heavy use. We assemble a few hundred punkers with hepatitis who checked into the Liverpool General, locate a comparable group of relatively healthy punkers, and inquire about safety pin and drug use. The data are arrayed in Table 12-1. Association of Hepatitis B among Drug Users and Pin Users Hepatitis B By inspection, there certainly appears to be an association between safety pins and hepatitis B. But there is also a relation between pin use and drug use 54 of nondrug users use pins, compared to 59 of heavy drug users who also use pins. Because both drug use and pin use are associated with hepatitis B, simply adding the subtables together to calculate an...

Conclusions and Perspectives

Vaccination against HCV faces more difficult problems because of the genetic heterogeneity virus and its great anti- genic variability. Therefore, an HCV vaccine is not yet available. Vaccines against HPV have been prepared by using the nonstructural proteins E6 and E7 as well as virus-like particles made of the structural proteins L1 and L2 from HPV-16 and HPV-18. Rodents immunized with these proteins become resistant to papillomavirus tumorigenesis.30,262,263 These HPV vaccines are currently being tested in clinical trials. A vaccine against EBV was prepared with the major envelope glycopro-tein gp350, the main component of the EBV envelope antigen, which functions as a viral receptor for virus attachment to susceptible cells. This vaccine protected cottontop tamarin monkeys from B-cell lymphomas induced by EBV,264,265 but it has not been adopted for use. A recombinant vaccinia vector containing a safety-modified SV-40 Tag sequence was constructed.266 Such modified Tag excludes the...

Polyclonal Immunoglobulins

The ability of polyclonal human immunoglobulin IgG (HIG) to detect inflammatory foci was a serendipitous discovery. Passive diffusion is probably the primary mechanism of uptake with retention in the interstitium due to the large molecular size (169 kD). HIG can be labeled with either 99mTc or mIn. However, interest in radiolabeled immunoglobulins has waned considerably after reports that viral infections (most notably hepatitis C) have been transmitted with therapeutic doses.

Prophylactic Vaccines

The ultimate expression of medical success is prevention of a disease, and subsequently, its total eradication. It was not until the last case of endemic smallpox occurred in Somalia in 1977, with eradication of the disease declared shortly thereafter that vaccination was recognized as the means to eliminate diseases from the planet. The first mass vaccination strategy to prevent a cancer was the hepatitis B vaccine. Although, it has taken 20 years to demonstrate impact on hepatoma rates, the success of this preventive vaccine is now clear. Because the etiology of cervical cancer is infectious in nature, interfering with HPV infection with a prophylactic vaccine should theoretically prevent development of the disease and potentially achieve total eradication of cervical cancer and other HPV-related cancers. However, prophylaxis does not benefit those with preexisting disease. This is a significant issue because of the considerable burden of HPV infection worldwide. Furthermore, purely...

Bunyavirus Minireplicon System In Mosquito Cells

In order to probe the molecular mechanisms that account for the difference in infection outcomes between mammalian and insect cells, recently we have established a 'minireplicon' system in Aedes albopictus C6 36 cells (Fig. 4 A. Kohl and others, unpublished). C6 36 cells expressing bacteriophage T7 RNA polymerase (C6-IBT7 3 cells) were selected following transfection with a plasmid encoding the polymerase gene and a blasticidin resistance gene. Bunyamwera virus proteins could be expressed in these cells by transfecting plasmids containing the viral coding sequences under T7 promoter control and baculovirus translational enhancers (Scheper et al., 1997) to ensure efficient expression. The minireplicon plasmid contained a negative-sense Renilla luciferase gene flanked by Bunyamwera virus non-coding sequences under control of the T7 promoter. The 3'-end of the minireplicon transcript was generated by hepatitis delta virus ribozyme-mediated self cleavage.

Bioaerosols and Disease Donald E Gardner PhD

All forms of life harbor microorganisms in and on their bodies. Generally, the agents of infectious diseases are transmitted from one species to another or from one individual of a species to another member of the same species. Certain individuals may be carriers who harbor pathogenic agents in their bodies but show no signs of illness, that is, the carrier is infected but is asymptomatic. Human carriers play an important role in the spread of diphtheria, epidemic meningitis, hepatitis B, streptococcal infections, and pneumonia, and such individuals can be considered living reservoirs from which microbes can be dispersed. Consequently, many normal human activities generate airborne microbes during sneezing, coughing, talking, shedding of skin flakes, surgical and dental processes, and activities such as cleaning and sweeping (20, 27, 33). It has been estimated that a healthy individual maintains about 1012 bacteria on the skin, 1010 in the mouth, and 1014 in the alimentary canal (34)....

Description Of The Procedure

Human immunodeficiency virus type 1 (HIV-1) RNA levels in plasma, hepatitis C virus (HCV) RNA in serum, and hepatitis B virus (HBV) DNA in serum can be quantified using a solid phase nucleic acid hybridization assay (Quantiplex ) based on bDNA signal amplification technology, shown in Fig. 1. RNA or DNA is detected in a sample based on a unique solution-phase sandwich hybridization assay coupled with signal amplification employing

Phenothiazine Derivatives

At the CTZ by inhibiting dopaminergic transmission. They also decrease vomiting caused by gastric irritants, suggesting that they inhibit stimulation of peripheral vagal and sympathetic afferents. Sedation will frequently occur following their administration. Patients also may have problems with acute dystonic reactions, orthostatic hypotension, cholestatic hepatitis, and blood dyscrasias.

Clinical presentation

Over 10 per cent have ascites, and this correlates with increased liver dysfunction. Because HELLP may occur in the absence of the usual clinical findings of pre-eclampsia, a non-obstetric diagnosis such as hepatitis, gastroenteritis, or gallbladder disease is often made.

Special Issues In Organ Transplantation

The most salient psychosocial issue and controversy in liver transplantation is the transplantation of patients with alcoholic liver cirrhosis. There is slowly emerging data on the most important questions initially asked about liver transplantation in alcoholics. These scientific questions have always existed in the context of the larger questions of ethics, moralization and the reality of public perception. The scientific questions have been about survival, return to drinking and quality of life. The ethical question goes as follows if we have a scarce resource like donor livers should we allow alcoholics who presumably shoulder a greater responsibility for their illness to receive equal consideration for transplantation The fact is that alcohol cirrhosis and recently hepatitis C, which in some cases is the consequence of IV drug abuse, are the most common causes for cirrhosis. As the waiting lists rise, it will be important to have data to support the rationale in transplantation...

Positive Stranded RNA Viruses Make Polyproteins

Picornaviruses are small, spherical single-stranded RNA viruses. They include polio, common cold, hepatitis A, and foot and mouth disease. Their genome is long enough for about a dozen genes. Since they are positive-strand RNA viruses, their RNA can be directly used as mRNA. The viral RNA does have a poly(A) tail attached to its 3'-end but has no cap. Instead a protein, the Vpg protein, is attached covalently to the 5'-

Viral RNAdependent RNA polymerases 731 Poliovirus polymerase

Poliovirus, the prototype picornavirus , is among the most diverse and oldest known viruses and is closely related to several medically important viruses, including rhinoviruses, hepatitis A virus, coxsackieviruses, and echoviruses. RNA replication by poliovirus RNA Pol is distinct from eukaryotic RNA Pol II in that it does not involve a nuclear phase, occurring within large protein complexes associated with the membranes of virus-induced cyto-plasmic vesicles.39

Interpretation of Results

Clinical cutoff values for each of the assays were set by assessing the signal generated by a large number of negative samples and determining the level above which the assay could reliably distinguish a negative from a positive sample. Currently, the standard curve for HCV is 3.5 x 105 to 5.7 x 107 RNA equivalents ml (the HCV assay uses 50 A per well) for HBV, the curve is 7 x 105 to 4.5 x 109 DNA equivalents ml (the HBV assay uses 10 fil per well) for HIV, the curve is 1 x 104 to 1.6 x 106 RNA equivalents ml (the HIV assay uses 1 ml per well in a centrifuged pellet). The sensitivities are determined by studying populations of individuals known to be infected with each particular virus, as discussed subsequently. Sensitivity comparisons of populations are much more useful than molecular comparisons, since every laboratory uses different standards. The specificity of all the assays is greater than 98 .

Bloodborne Pathogens In the Workplace Debra L Hunt Jerry J Tulis MD

4 Hepatitis Viruses At the time of writing, at least six viruses are known to cause hepatitis hepatitis A, B, C, D, E, and G. Epidemiologically, the viruses can be divided into two groups according to mode of transmission. The hepatitis A and E viruses are transmitted primarily by the fecal-oral route. The hepatitis B, C, D, and G viruses are transmitted by direct contact with blood or body fluids. Hepatitis B and C viruses are frequently responsible for occupational infections. 4.1 Hepatitis B Virus (HBV) Hepatitis B virus is transmitted parenterally, sexually, and perinatally, and is the major cause, worldwide, of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. High risk groups in industrialized countries include intravenous drug users, homosexual men, and those with multiple sexual partners (113). Others at substantial risk of infection include hemodialysis patients, institutionalized patients, and healthcare workers with occupational exposure to blood (114)....

Mechanism of action

To prevent virus transmission, fibrin sealants are subjected to a variety of chemical treatments to ensure a safe product, free from virus. At present, fibrinogen can be obtained from individual units of blood plasma that are previously tested for the associated risk of hepatitis and human immune deficiency virus (HIV). In addition, for viral inactivation, commercial solutions are purified using a two-step vapor-heating method at 60 and 80 C, or other methods such as pasteurization (10 h in an aqueous solution at 60 C), detergent treatments, nanofiltration, chromatography, ultraviolet C light, etc. A combination of these treatments is preferable because none of them is 100 effective. The methods employed by the manufacturers offer a sufficient margin of safety against HIV and hepatitis B and C viruses. In 2000, Gosalbez et al. reported a parvovirus B19 transmission attributed to the use of fibrin sealant 3 , but there are no cases of serious viral transmission reported in the...

Use of immunoglobulin

Intravenous polyvalent immunoglobulin widely used as replacement therapy in immunodeficiencies, for Kawasaki disease to prevent the formation of coronary microaneurysms, and also as non-specific agent for reticuloendothelial blockade in immune cytopenias, chiefly (and usually unnecessarily) in childhood ITP. Can get immunoglobulin with particularly high titre against RSV, HZV and hepatitis B. Usually this is for intramuscular use only and should not be given IV due to risk of complement activation. IVIg has transmitted hepatitis C in the past due to poor virus inactivation procedures, so should not be used in trivial conditions.

Evolution of RTcontaining viruses

RT can rapidly evolve and increase the diversity of genetic populations via error-prone replication. Homologous elements of RTs are encoded in the genomes of many retroviruses1 such as human immunodeficiency virus (HIV) hepadnaviruses such as hepatitis B virus (HBV)4,5 plant and animal DNA viruses such as cauliflower mosaic viruses4 retrotransposons6-8 and mitochondrial group II introns.9 Retroviral and hepadnaviral RTs have been the main focus of RT research because HIV and HBV cause worldwide pandemic diseases spread through transfusion of blood and or body fluid. HBV is a human pathogen that causes acute and chronic hepatitis B, the major cause of liver disease and liver cancer. Unlike HIV, HBV does not need to integrate its viral DNA into host cell DNA for replication. It is a double-stranded DNA virus that replicates via an RNA intermediate (Figure 8.1B). After entering a hepatocyte and uncoating, viral plus-strand DNA is synthesized to join minus-strand DNA and to form...

Arthropodrelated problems in poor urban and rural settings

Dangerous substances with which people can come into contact it is the principal source of the pathogenic organisms of many communicable diseases, particularly infections of the intestinal tract (WHO 1988a,b). The house fly Musca domestica and several other flies in the families Muscidae, Calliphoridae, and Sarcophagidae are very efficient 'mechanical' vectors of pathogens (viruses, bacteria, protozoa, and helminth eggs) from human faeces to human food. These flies are often most serious pests in warm weather when they can reach high population densities. They breed in decaying food and garbage and are attracted to human food, human faeces, dead animals, garbage, rotting vegetation, and other organic material. Removal, destruction or protection of potential fly breeding sites is likely to effectively reduce the incidence of a number of diseases such as cholera, hepatitis A, and amoebiasis and other intestinal parasites.

Introduction Wide Scope ofVirogenomics

The virogenomics revolution has had impact on several additional fronts. In molecular epidemiology, it has allowed the precise molecular identification of viruses isolated in the field, leading to the calculation of genetic distances from viral relatives and to the establishment of phylogenetic relationships among viruses displaying various degrees of relatedness (further discussed in the next sections). This information, in turn, can often help in tracing the possible origin of a viral disease outbreak and in defining the molecular changes (mutation, recombination, segment reassortment) associated with the emergence and progression of a viral disease. Such progression can have different time-size scales. It may relate to an outbreak on a small community scale, or up to a worldwide scale, as in the current AIDS or many historical influenza pandemics. It may also relate to the progression of viral disease symptoms and associated viral genomic changes within single infected individuals,...

Virogenomics Through Microarrays

Other examples of the use of DNA microarrays in virology include the typing and subtyping of influenza viruses 94 , rotaviruses 95 , or other viruses 96 , the detection of molecular recombination in polioviruses 97 , and the determination of genomic RNA structure in HIV-1 and hepatitis C virus genomes 98, 99 . Therefore, microarray-based technologies constitute one of the most promising tools in the investigation of the wide scope of virogenomics. H. Romero, B. Khan and J. Cristina. 2004. Evidence of intratypic recombination in natural populations of hepatitis C virus. J. Gen. Virol. 85 31-37. L. Lopez, S. Vasquez, L. Garcia-Aguirre and A. Chunga. 2005. Hepatitis C virus F protein sequence reveals a lack of functional constraints and a variable pattern of amino acid substitution. J. Gen. Virol. 86 115-120. C. Bressollette-Bodin, S. Billaudel and J. Cristina. 2003. Evidence of recombination in natural populations of hepatitis A virus. Virology 311 51-59. J. Guardia and J. Gomez. 2004....

Clinical symptoms in the immunocompetent individual

These nodes usually disappear within a month but can persist for a longer period in some individuals. Enlarged nodes in the abdomen can cause abdominal pain. Retinochoroiditis, usually unilateral, may occur in cases of an acute, acquired infection. Pneumonitis, myocarditis, pericarditis, hepatitis, and central nervous system involvement may occur, but is rare (Sherman and Nozik 1992). Pulmonary toxoplasmosis has been described in immunocompetent patients (Pomeroy and Filice 1992). Shortness of breath and cough are the most common symptoms, together with fever and rales. Lymphadenopathy

Production of factor VIII

Native factor VIII is traditionally purified from blood donations first screened for evidence of the presence of viruses such as hepatitis B and HIV. A variety of fractionation procedures (initially mainly precipitation procedures) have been used to produce a factor VIII product. The final product is filter-sterilized and filled into its finished product containers. The product is then freeze-dried and the containers are subsequently sealed under vacuum, or are flushed with an inert gas (e.g. N2) before sealing. No preservative is added. The freeze-dried product is then stored below 8 C until shortly before its use.

Infections and their prevention

Viral infection (herpesvirus and cytomegalovirus) of the liver occurs in about 10 per cent of patients between the second and sixth postoperative week the risk depends on the serological states of the donor and the recipient. Severity ranges from being virtually asymptomatic to a systemic illness with fever, arthralgia, malaise, hepatitis, pneumonitis, and enteritis. Diagnosis is by serology and liver biopsy. Treatment involves a reduction in immunosuppression and the antiviral agent

Evolutionary Significance

Evidence in support of their putative ancient origin also derives from the distinct enzymatic properties of their RTs, such as the mechanistic similarity of the pMaur-RT to RNA-dependent RNA polymerases. The finding that the pFOXC retroplasmids have 3' terminal repeats similar to those of chromosomal telomeres and replicate via reverse transcription makes them leading contenders to be precursors of telomerase (Walther and Kennell 1999). In addition, retroplasmid clothespin DNAs contain a 5'-linked protein, suggesting a potential relationship to hepadnaviruses (e.g., hepatitis B virus) that have covalently attached terminal proteins that serve as primers for cDNA synthesis (reviewed in Ganem and Schneider 2001). These properties help to justify the position of retroplasmids at the base of retroelement phylogeny and the collective features of circular and linear retroplasmids suggest that they are related to primordial genetic elements that could have been a common ancestor of...

IIA General Aspects of NO in the Liver

Cells in the liver can be divided into the hepatic parench-ymal cells (hepatocytes) and the hepatic nonparenchymal cells, which are further subdivided into endothelial cells, smooth muscle cells, Kupffer cells, and hepatic stellate cells. Both hepatic parenchymal cells and hepatic nonparenchymal cells can express iNOS, whereas eNOS is constitutively expressed in hepatic endothelial cells. Although iNOS is not thought to be expressed constitutively in healthy liver, it is readily upregulated in the liver under a number of disease conditions, including ischemia-reperfusion injury, cirrhosis, hepatitis, and liver regeneration (1-4). The iNOS is also upre-gulated in vitro in hepatocytes and Kupper cells in response to endotoxin, proinflammatory cytokines, such as tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1 ), and interferon , as well as their combinations (5). These stimuli often act synergistically to induce iNOS expression however, IL-1 alone is an effective stimulator of iNOS...

Applications of nucleotides in the research of reverse transcriptase

Two classes of RT inhibitors are used in the clinical treatment of AIDS nucleoside nucleotide analog reverse transcriptase inhibitors (NRTIs), and nonnucleoside analog reverse transcriptase inhibitors (NNRTIs). Some NRTIs are also being used for hepatitis B virus infection. These two types of RT inhibitors and HIV protease inhibitors are used in combination therapies to achieve maximum potency at a tolerable level of toxicity.

Studies of TPMT in Rheumatology

Some of the variation in AZA metabolism can be accounted for by the fact that there is clear variation in TPMT enzyme activity between individuals the genetic basis for this has been determined. The TPMT gene, localized to chromosome 6p22.3, displays at least eight polymorphisms associated with reduced enzyme activity. The nonmutant gene is designated TPMT*1, and mutated genes are assigned as TPMT *2-*6. In Caucasians the most common polymorphism associated with reduced enzyme activity is *3A point mutation 460 (G A) and 719 (A G) (60). The isolated mutation at position 719 (*3C) is a common cause of low activity in African populations (61,62). Approximately 89 of the white Caucasian subjects are homozygous (two wild-type alleles) for the inherited trait of high TPMT activity. Eleven percent are heterozygous (one wild type and one variant allele) and have intermediate TPMT activity, while approximately 0.3 are homozygous for the trait of very low or absent activity (two variant...

Quantification of Viral RNA Using an Internal Control

Workers (1992) used cRT-PCR to monitor hepatitis C virus (HCV)-infected patients receiving interferon-a therapy. Cross-sectional studies involving HIV-l-infected individuals at different disease stages have confirmed the correlation between increases in HIV-1 RNA load and disease progression (Bagnarelli et al., 1992 Piatak et al., 1993b).

Chapter s nutrition and gastrointestinal system

C Patients who develop fulminant hepatic failure as a result of hepatitis B virus infection (when compared with patients who do not progress to hepatic failure) tend to have earlier appearance of antibodies against hepatitis B surface antigen. Also, they have earlier appearance of antibodies against hepatitis B, E-antigen, and more rapid clearance of the hepatitis B surface antigen. (Rogers MC, et al. Textbook of Pediatric Intensive Care, 3rd Edition pp. 1179-1181.)

Hepatotoxicity To The Overall Burden Of Liver Disease

Drugs are responsible for between 2 and 6 of jaundice and about 10 of cases of ''acute hepatitis'' (Lewis and Zimmerman, 1989 Whitehead et al., 2001). In industrialised nations such as the United States, France and Denmark ADRs account for up to 20 of cases of acute hepatic failure, while it is less common (5 ) in tropical countries such as India (Acharya et al., 1996 Ostapowicz et al., 1999). Drug-induced chronic hepatitis has been considered rare, even though it accounts for up to 6 of all chronic hepatitis (Aithal and Day, 1999). Drug hepatotoxicity almost certainly remains an important and often neglected cause of cholestasis, although its relative frequency among other cholestatic syndromes has not been reported. Drugs probably contribute to the aetiology of less than 1 of all liver tumors (Farrell, 1994).

Aspartate and alanine aminotransferases

These enzymes are released when there is cell damage causing an increase in permeability of the cell membrane or cell necrosis. The main value of the aminotransferases is in detecting hepatocellular damage and monitoring the patient's progress. The levels rapidly return to normal following resolution of the factors causing hepatocellular damage. Because they are so non-specific, raised levels of these enzymes are of little value alone in generating a differential diagnosis however, a very high level (greater than 1000 IU L) is strongly suggestive of acute hepatitis of viral, drug, or ischemic origin.

Galactose elimination capacity

Galactose is eliminated from the liver via a phosphorylation pathway involving galactokinase. When this enzyme is saturated, the hepatic galactose clearance follows zero-order kinetics and can be used as a determinant of hepatic function. It has been shown in animals to be proportional to the functioning mass of hepatocytes. In this test 0.5 g kg of galactose is injected intravenously (Iygstrup.J966) and galactose levels are then measured in the serum to determine clearance between 20 and 50 min following injection. Values below 2 mg kg min are incompatible with survival and probably relate to extrahapatic galactose clearance. This test has been shown to be able to predict survival in patients with primary biliary cirrhosis and to correlate with outcome following interferon treatment for hepatitis B.

Liver DiseasesA Variety of Conditions

There are numerous reasons for impairment of the hepatic function. In the western world, chronic alcohol abuse is one of the main causes of liver disease and can cause steatosis, alcohol hepatitis, and cirrhosis. Hepatitis is mainly caused by viruses, hepatotoxic substances, and autoimmune diseases. The condition is characterized by cell necrosis and inflammation in the liver. All forms give the same alterations of the liver, including simultaneous necrosis and degeneration of hepatocytes, infiltration of mononuclear cells, degeneration of Kupffer cells, and varying degree of cholestasis. Cirrhosis is not a disease in itself but a stage in the course of inflammatory liver diseases. Cirrhosis can be caused by liver damage resulting from alcoholism, hepatitis B and hepatitis C, drugs, metabolic disorders, prolonged cholestasis, etc. Cirrhosis is characterized by increased presence of fibrous tissue, destruction of the lobular architecture and sinusoidal network, and nodular...

Management Of Idiosyncratic Hepatotoxicity

Management of acute hepatic failure secondary to idiosyncratic hepatic reaction is similar to that of viral hepatitis. The overall mortality of drug-induced hepatic failure (excluding paracetamol overdose) appears to be higher than that for viral hepatitis. Despite the availability of liver transplantation, the mortality from severe hepatotoxi-city ranges from 2 to 7 with drugs such as pemoline, ketoconazole and diclofenac, up to 50 in the case of halothane (Lewis et al., 1984 Nehra et al., 1990 Banks et al., 1995 Lo et al., 1998). Corticosteroid treatment has not been shown to be beneficial in the management of drug-induced hepatitis. There is no clear evidence that urso-deoxycholic acid therapy changes outcome in chronic cholestasis.

Other antituberculosis agents

Isoniazid is given orally at a dose of 5 mg kg, which is doubled in tuberculous meningitis. It is metabolized in the liver and dosage is not reduced in renal failure. Hepatitis occurs in 1 per cent of patients, but peripheral neuropathy can be prevented by giving pyridoxine. Pyrazinamide is often combined with rifampin and isoniazid. It is given orally and can be used to treat meningitis. Hepatotoxicity can occur. Ethambutol is bacteriostatic and is widely distributed after oral administration. The dose is reduced in renal failure. Optic neuritis (loss of color vision) is an important adverse effect which prevents its use in the unconscious. Streptomycin, like other aminoglycosides, is ototoxic and nephrotoxic, and serum levels must be assayed. However, it can be given parenterally with rifampin and isoniazid.

Administering Different Types and Dosages of Cytokines and Their Effects on Sleep

Administration of TNF-a, IL-ip, or IL-18 increases the length of NREM sleep time and decreases the duration of REM sleep. Patients treated with recombinant or purified cytokines for specific forms of cancers or viral infections such as hepatitis B or C become somnolent (Papanicolaou, Wilder, Manolagas, and Chrousos 1998).