Hepatitis: US Non-Military

Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, Csako G. · National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland 20892, USA. · Ann Intern Med. · Pubmed #18378948 links to  free full text

Abstract: BACKGROUND: Lamivudine is increasingly being used to prevent hepatitis B reactivation in patients with cancer who test positive for hepatitis B surface antigen (HBsAg) and are undergoing chemotherapy. PURPOSE: To determine whether preventive lamivudine reduces chemotherapy-induced hepatitis B virus (HBV)-related morbidity and mortality in patients with cancer who test positive for HBsAg. DATA SOURCES: MEDLINE, Ovid MEDLINE, TOXNET, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched in all languages until June 2007. STUDY SELECTION: Clinical trials and cohort studies that reported the efficacy of preventive lamivudine versus control on HBV reactivation in patients who tested positive for HBsAg and were receiving chemotherapy were included. Additional requirements included minimum sample size (>5 participants per treatment group) and reported HBV-related morbidity and mortality data. DATA EXTRACTION: Two investigators independently did literature searches and data extraction, and 2 other investigators independently confirmed study eligibility and data retrieval. DATA SYNTHESIS: Fourteen studies (2 randomized, controlled trials; 8 prospective cohort studies; and 4 retrospective cohort studies) met the predefined criteria for analysis. There were 275 patients in the preventive lamivudine group and 475 control participants for the primary end point of HBV reactivation. With preventive lamivudine, the relative risk for both HBV reactivation and HBV-related hepatitis ranged from 0.00 to 0.21. None of the patients in the preventive lamivudine group developed HBV-related hepatic failure (0 of 108 patients vs. 21 of 162 patients), and only 4 deaths were attributable to HBV (4 of 208 patients vs. 27 of 394 patients) in the preventive lamivudine group. Lamivudine was well tolerated, and no adverse effects were noted. LIMITATIONS: The studies included in the meta-analysis did not consistently report all of the outcomes of interest. Sample sizes were small and only 2 studies had a randomized, controlled design. CONCLUSION: Preventive therapy with lamivudine for patients who test positive for HBsAg and are undergoing chemotherapy may reduce the risk for HBV reactivation and HBV-associated morbidity and mortality.

Li TK. · National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland 20892-9304, USA. · J Gastroenterol Hepatol. · Pubmed #18336658 No free full text.

Abstract: The aim of the present review was to: (i) highlight epidemiological and other studies that have generated important data on the harmful patterns of drinking that increase the risk for chronic diseases, including alcohol dependence, and on the mechanisms by which alcohol produces and, in some instances, may protect against damage; and (ii) discuss a conceptual basis for quantifying risk criteria for alcohol-induced chronic disease based on the quantity, frequency, and pattern of drinking. The relationship between heavy drinking and risk for adverse health conditions such as alcoholic liver disease (ALD), dementia, and alcohol dependence is well known. However, not everyone who drinks chronically develops ALD or dementia, and the major risk factors for disease development and the mechanisms by which this occurs have remained unclear. Large-scale, general population-based studies have provided the evidence by which quantifying the frequency of a pattern of high-risk drinking can be related directly to risk and the severity of alcohol dependence. Cellular and molecular biology studies have identified the major pathways of alcohol metabolism and how genetics and the environment can interact in some individuals to further increase the risk of organ damage. Extant databases should allow scientists and clinicians jointly to develop the framework for quantifying the drinking patterns that increase the risk of alcohol-induced organ pathologies, to develop clinical practice guidelines, such as those used to diagnose other common complex diseases (e.g. diabetes and hypertension), and to propose future studies for refining such guidelines. Attention must be paid to comorbid conditions such as hepatitis B and C infections, HIV, obesity, and environmental exposures other than alcohol. Developing trait and state biomarkers is critical to the process of discovery and to fulfilling the promise of personalized medicine.

Choudhury D, Luna-Salazar C, Anonymous00415. · Internal Medicine at the University of Texas Southwestern Medical School at Dallas, TX, USA. · Nat Clin Pract Nephrol. · Pubmed #18285747 No free full text.

Abstract: The complex care that must be provided for patients with renal disease might interfere with provision of basic preventive measures in this population. Preventive health care, including infection screening and prophylaxis, vaccinations, management of blood glucose and lipid levels, and cancer screening, is important, as it might decrease acute morbidity and mortality. This Review highlights useful preventive and health maintenance strategies for patients with chronic kidney disease and those with end-stage renal disease.

Loomba R, Liang TJ. · Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MA, USA. · Antivir Ther. · Pubmed #18284181 No free full text.

Abstract: Hepatitis B virus (HBV) infection is the leading cause of chronic liver disease and hepatocellular carcinoma worldwide. Approximately 350 million individuals are infected with HBV and >500,000 deaths per year can be attributed to HBV. Although universal vaccination has reduced HBV incidence in many countries, it still remains a major public health problem, especially in parts of Asia and Africa. Improved understanding of HBV virology and virus-host interactions has revolutionized chronic hepatitis B therapy in the past two decades. Development of oral nucleoside/nucleotide analogues heralds a new era of safe and effective treatment of this disease. On the basis of these advances, new guidelines for the treatment of chronic hepatitis B have been issued. Successful long-term treatment of chronic hepatitis B may rest on combination therapy that is based on molecular approaches targeting various stages of the HBV life-cycle. In this review, we summarize the current modalities and highlight important issues in the treatment of chronic hepatitis B monoinfection.

Pacher P, Gao B. · Laboratory of Physiological Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, Maryland 20892-9413, USA. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #18239059 links to  free full text

Abstract: Recent studies have implicated dysregulation of the endocannabinoid system in various liver diseases and their complications (e.g., hepatitis, fibrosis, cirrhosis, cirrhotic cardiomyopathy, and ischemia-reperfusion), and demonstrated that its modulation by either cannabinoid 2 (CB(2)) receptor agonists or CB(1) antagonists may be of significant therapeutic benefits. This review is aimed to focus on the triggers and sources of endocannabinoids during liver inflammation and on the novel role of CB(2) receptors in the interplay between the activated endothelium and various inflammatory cells (leukocytes, lymphocytes, etc.), which play pivotal role in the early development and progression of inflammatory and other liver diseases.

Purcell RH, Emerson SU. · Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892-8009, USA. · J Hepatol. · Pubmed #18192058 No free full text.

Abstract: Although hepatitis E was recognized as a new disease in 1980, the virus was first visualized in 1983 and its genome was cloned and characterized in 1991, the disease is probably ancient but not recognized until modern times. Hepatitis E is the most important or the second most important cause of acute clinical hepatitis in adults throughout Asia, the Middle East and Africa. In contrast, hepatitis E is rare in industrialized countries, but antibody (anti-HEV) is found worldwide. HEV is a small round RNA-containing virus that is the only member of the genus Hepevirus in the family Hepeviridae. Although similar to hepatitis A virus in appearance, there are significant differences between the two viruses. Hepatitis E is principally the result of a water-borne infection in developing countries and is thought to be spread zoonotically (principally from swine) in industrialized countries. Because diagnostic tests vary greatly in specificity, sensitivity and availability, hepatitis E is probably underdiagnosed. At present, control depends upon improved hygiene; a highly efficacious vaccine has been developed and tested, but it is not presently available.

Modi AA, Liang TJ. · The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. · Oral Dis. · Pubmed #18173443 No free full text.

Abstract: Hepatitis C is a major cause of chronic liver disease. It has been recognized as a global health problem because of the progression to cirrhosis and hepatocellular cancer. Chronic hepatitis C is usually asymptomatic but can cause considerable liver damage before its recognition. This review discusses the natural history, clinical features, diagnosis, therapy, treatment responses and the side effects associated with the treatment of hepatitis C.

Zakhari S, Li TK. · National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9304, USA. · Hepatology. · Pubmed #18046720 No free full text.

Abstract: More than 70% of alcohol is consumed by 10% of the population in the United States. Implicit in this statistic is that tremendous variation in the pattern of drinking (quantity, frequency, and duration) exists among alcohol consumers. Individuals who are binge or chronic drinkers will have different health outcomes than social drinkers. Therefore, knowing the pattern of drinking will shed light on how severely individuals are alcohol-dependent and on the extent of liver damage. Thus, these parameters assume particular relevance for the treatment-providing physician. Genetic factors contribute substantially to differences in alcohol metabolism. Variations in the activities of the alcohol-metabolizing enzymes, cytosolic alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase, in part determine blood alcohol concentration, thereby contributing to the predisposition to becoming alcohol-dependent and to susceptibility to alcohol-induced liver damage. Chronic alcohol consumption induces cytochrome P450 2E1, a microsomal enzyme that metabolizes alcohol at high concentrations and also metabolizes medications such as acetaminophen and protease inhibitors. Alcohol metabolism changes the redox state of the liver, which leads to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. The quantity and frequency of alcohol consumption severely impact the liver in the presence of comorbid conditions such as infection with hepatitis B or C and/or human immunodeficiency virus, type 2 diabetes, hemochromatosis, or obesity and thus have implications with respect to the extent of injury and response to medications. Conclusion: Knowledge of the relationships between the quantity, frequency, and patterns of drinking and alcoholic liver disease is limited. A better understanding of these relationships will guide hepatologists in managing alcoholic liver disease.

Emerson SU, Purcell RH. · Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. · Pediatr Infect Dis J. · Pubmed #18043454 No free full text.

This publication has no abstract.

Gonzalez FJ, Shah YM. · National Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA. · Toxicology. · Pubmed #18006136 No free full text.

Abstract: Peroxisome proliferator chemicals are classic non-genotoxic carcinogens. These agents cause liver cancers when chronically administered to rats and mice. Peroxisome proliferators include the widely prescribed lipid and cholesterol lowering fibrate drugs. In contrast to the results in rodents, there is no evidence that fibrates are associated with elevated risk of liver cancer or any other neoplasms in humans thus indicating a species difference in the hepatocarcinogenic response. The biological effects of peroxisome proliferators are mediated by the peroxisome proliferator-activated receptor (PPAR)alpha. Pparalpha-null mice are resistant to all of the pleiotropic effects of peroxisome proliferators, including cell proliferation and hepatocarcinogenesis. The mechanism of hepatocellular proliferation involves downregulation of the microRNA let-7c gene by PPARalpha. Let-7c controls levels of proliferative c-myc by destabilizing its mRNA. Thus, upon suppression of let-7c, c-myc mRNA and protein are elevated resulting in enhanced hepatocellular proliferation. In contrast, PPARalpha-humanized mice, that respond to Wy-14,643 by lower serum triglycerides and induction of genes encoding fatty acid metabolizing enzymes, are resistant to peroxisome proliferator-induced cell proliferation and cancer. These mice do not exhibit downregulation of let-7c gene expression thus forming the basis for the resistance to hepatocellular carcinogenesis.

Tomer Y, Blackard JT, Akeno N. · Division of Endocrinology, Cincinnati VA Medical Center, USA. · Endocrinol Metab Clin North Am. · Pubmed #17983936 links to  free full text

Abstract: Interferon alpha (IFN alpha) is the cornerstone therapeutic agent for chronic hepatitis C virus (HCV) infection. Prospective studies have shown that up to 15% of HCV patients receiving IFN alpha develop clinical thyroid disease, and up to 40% become thyroid antibody positive. In some cases IFN-induced thyroiditis (IIT) may result in discontinuation of interferon therapy; thus, IIT represents a major clinical problem for hepatitis C patients receiving IFN alpha therapy. Recently, the mechanisms leading to the development of IIT have begun to be unraveled. It is now clear that HCV itself plays a role in the disease. Moreover, recent data suggest the IFN alpha precipitates thyroiditis by both immune modulatory mechanisms and direct thyroid toxic effects. Genetic factors also play a major role in the etiology of IIT. IIT can manifest both as clinical autoimmune thyroiditis (ie, Hashimoto's thyroiditis and Graves' disease) and as nonautoimmune thyroiditis (ie, destructive thyroiditis). Early detection and therapy of these conditions are important to avoid complications of thyroid disease such as cardiac arrhythmias. This article reviews the epidemiology and clinical manifestations of IIT and the mechanisms causing IIT, focusing on the role of HCV.

Kramer JR, Giordano TP, El-Serag HB. · Houston Center for Quality of Care and Utilization Studies, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA. · Clin Gastroenterol Hepatol. · Pubmed #17981246 No free full text.

Abstract: BACKGROUND & AIMS: We systematically reviewed the literature examining the association of human immunodeficiency virus (HIV) and antiretroviral therapy (ART) with liver disease in patients with hepatitis C virus (HCV) infection. METHODS: PubMed was searched for studies examining hepatic fibrosis, cirrhosis, decompensated liver disease, hepatocellular carcinoma, and liver-related death. Thirty-nine reports (describing 34 unique studies) met inclusion criteria. Information was abstracted on study design, sampling frame, inclusion/exclusion criteria, sample size, results, and covariates used for adjustment. Because of the heterogeneity among study designs, a meta-analysis was not conducted. RESULTS: Nine of the 12 cross-sectional studies showed a statistically significant association between HIV co-infection and fibrosis or cirrhosis, whereas 7 retrospective cohort studies were inconsistent. Six studies examined decompensated liver disease as the outcome: 5 of these found a significantly increased risk in patients with HIV co-infection. The 7 studies examining liver-related death showed a trend toward an association with HIV co-infection, although only 4 were statistically significant. Four studies examined the effect of HIV on hepatocellular carcinoma, 2 of which found no association. Of 10 studies that investigated the effect of ART on the risk of liver disease, half reported a significant protective association. CONCLUSIONS: HIV co-infection is associated with an increased risk of advanced liver disease in hepatitis C virus-infected patients. Data on hepatocellular carcinoma are sparse, but an association is plausible given the increased risk of advanced liver disease. In contrast, data for an effect of ART are plentiful, but findings are inconsistent. More robust studies are needed on this topic.

Ku NO, Strnad P, Zhong BH, Tao GZ, Omary MB. · Department of Medicine, Palo Alto VA Medical Center and Stanford University Digestive Disease Center, Palo Alto, CA. · Hepatology. · Pubmed #17969036 No free full text.

Abstract: Keratin polypeptides 8 and 18 (K8/K18) are the cytoskeletal intermediate filament proteins of hepatocytes while K8/K18/K19 are the keratins of hepatobiliary ductal cells. Hepatocyte K8/K18 are highly abundant and behave as stress proteins with injury-inducible expression. Human association studies show that K8/K18 germline heterozygous mutations predispose to end-stage liver disease of multiple etiologies ( approximately 3 fold increased risk), and to liver disease progression in patients with chronic hepatitis C infection. These findings are supported by extensive transgenic mouse and ex vivo primary hepatocyte culture studies showing that K8 or K18 mutations predispose the liver to acute or subacute injury and promote apoptosis and fibrosis. Mutation-associated predisposition to liver injury is likely related to mechanical and nonmechanical keratin functions including maintenance of cell integrity, protection from apoptosis and oxidative injury, serving as a phosphate sponge, regulation of mitochondrial organization/function and protein targeting. These functions are altered by mutation-induced changes in keratin phosphorylation, solubility and filament organization/reorganization. Keratins are also the major constituents of Mallory-Denk bodies (MDBs). A toxin-induced K8>K18 ratio, and keratin crosslinking by transglutaminase-2 play essential roles in MDB formation. Furthermore, intracellular or cell-released K18 fragments, generated by caspase-mediated proteolysis during apoptosis serve as markers of liver injury. Therefore, K8 and K18 are cytoprotective stress proteins that play a central role in guarding hepatocytes from apoptosis. Keratin involvement in liver disease is multi-faceted and includes modulating disease progression upon mutation, formation of MDBs in response to unique forms of injury, and serving as markers of epithelial cell death.

Farci P, Chessa L, Balestrieri C, Serra G, Lai ME. · Department of Medical Sciences, University of Cagliari, Policlinico Universitario, Monserrato, Cagliari, Italy. · J Viral Hepat. · Pubmed #17958644 No free full text.

Abstract: Despite recent advances in the treatment of chronic viral hepatitis, therapy of chronic hepatitis D is not yet satisfactory. The only option currently available is interferon-alpha (IFN), whose efficacy is related to the dose and duration of treatment. However, the rate of sustained hepatitis D virus (HDV) clearance after a 1-year course with high doses of standard IFN is low. Better results have recently been reported with pegylated IFN both in IFN-naïve and in previous nonresponders to standard IFN, suggesting the use of pegylated IFN as a first-line therapy in chronic hepatitis D. Nucleoside analogues that inhibit hepatitis B virus (HBV) are ineffective against HDV and combination therapy with lamivudine or ribavirin has not shown significant advantages over monotherapy with either standard or pegylated IFN. Because the ultimate goal of treatment is eradication of both HDV and HBV, in responders IFN therapy should be continued as long as possible until the loss of hepatitis B surface antigen, adjusting the dose to patient tolerance. However, because side-effects are common, continuous monitoring is mandatory. Although the first results obtained with pegylated IFN have been encouraging, the rate of sustained virological response is still low and the rate of relapse high, emphasizing the need for developing novel classes of antivirals specifically interfering with the life cycle of this unique virus.

Aliyu ZY, Kato GJ, Taylor J, Babadoko A, Mamman AI, Gordeuk VR, Gladwin MT. · Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1662, USA. · Am J Hematol. · Pubmed #17910044 No free full text.

Abstract: Secondary pulmonary hypertension (PAH) has been shown to have a prevalence of 30% in patients with sickle cell disease (SCD) with mortality rates of 40% at 40 months after diagnosis in the United States. The burden of SCD is highest in sub-Saharan Africa, especially in Nigeria (West Africa), where approximately 6 million people are afflicted. The true global incidence, prevalence, and burden of SCD and its associated end organ complications however remain unknown. Chronic hemolysis represents a prominent mechanistic pathway in the pathogenesis of SCD-associated pulmonary hypertension via a nitric oxide (NO) scavenging and abrogation of NO salutatory effects on vascular function, including smooth muscle relaxation, downregulation of endothelial adhesion molecules and inhibition of platelet activation. Many known infectious risk factors for PAH are also hyperendemic in Africa, including Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), chronic hepatitis B and C, and possibly malaria. Interactions between these infectious complications and SCD-related hemolysis could yield an even higher prevalence of pulmonary hypertension and compound the existing global health systems challenges in managing SCD. Indeed, our preliminary analysis of African immigrants currently in the United States suggests that pulmonary hypertension represents a significant complication of SCD in the African subcontinent. There is clearly a need to include Africa and other parts of the world with high SCD prevalence in future comprehensive studies on the epidemiology and treatment of end organ complications of an aging SCD population world-wide.

McVicker BL, Tuma DJ, Casey CA. · Veterans Affairs Medical Center, Research Service (151), 4101 Woolworth Avenue, Omaha, NE 68105, USA. · World J Gastroenterol. · Pubmed #17854138 links to  free full text

Abstract: Chronic ethanol consumption is associated with serious and potentially fatal alcohol-related liver injuries such as hepatomegaly, alcoholic hepatitis and cirrhosis. Moreover, it has been documented that the clinical progression of alcohol-induced liver damage may be associated with an increase in hepatocellular death that involves apoptotic mechanisms. Although much information has been learned about the clinical manifestations associated with alcohol-related diseases, the search continues for a better understanding of the molecular and/or cellular mechanisms by which ethanol exerts its deleterious effects such as the induction of pro-apoptotic mechanisms and related cell damaging events. As part of the effort to enhance our understanding of those particular cellular pathways and mechanisms associated with ethanol toxicity, researchers over the years have utilized a variety of model systems. Recently, work has come forth demonstrating the utility of a hybrid cell line (WIF-B) as a cell culture model system for the study of alcohol-associated alterations in hepatocellular mechanisms. Success with such emerging model systems could aid in the development of potential therapeutic treatments for the prevention of alcohol-induced apoptotic cell death that may ultimately serve as a significant target in delaying the onset and/or progression of clinical symptoms of alcohol-mediated liver disease. This review article summarizes the current understanding of ethanol-mediated modifications in cell survival and thus the promotion of pro-apoptotic events with emphasis on analyses made in various experimental model systems, particularly the more recently characterized WIF-B cell system.

Singal AK, Anand BS. · James J Peters Bronx Veterans Affairs Medical Center, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10468, USA. · J Clin Gastroenterol. · Pubmed #17700425 No free full text.

Abstract: BACKGROUND: Since the discovery of the hepatitis C virus (HCV), extensive literature has emerged on alcohol and HCV interaction. GOAL: To understand the impact of alcohol and HCV infection on the severity of liver disease and the mechanisms of interaction between the two. STUDY: Of 1269 articles (1991 to 2006) searched through MEDLINE and cited cross references, 133 were thoroughly reviewed to assess: (a) prevalence of combined alcohol use and HCV, (b) severity of liver disease (c) treatment response, and (d) mechanisms of interaction between HCV and alcohol. Data on study design, patient demographics, diagnostic tests used, and study outcomes were extracted for critical analysis. RESULTS: Prevalence of HCV is 3-fold to 30-fold higher in alcoholics compared with the general population. Patients with HCV infection and alcohol abuse develop more severe fibrosis with higher rate of cirrhosis and hepatocellular cancer compared with nondrinkers. Increased oxidative stress seems to be the dominant mechanism for this synergism between alcohol and the HCV. Abstinence is the key to the management of liver disease due to HCV and alcohol. Data have shown that lower response rates to interferon in alcoholics with HCV infection are likely due to noncompliance. CONCLUSIONS: Alcoholics with HCV infection have more severe liver disease compared with nondrinkers. Patients should be encouraged to enroll in rehabilitation programs so as to improve treatment adherence and response.

Klein HG, Spahn DR, Carson JL. · Department of Transfusion Medicine, National Institutes of Health, Bethesda, Maryland 20892, USA. · Lancet. · Pubmed #17679019 No free full text.

Abstract: Every year, about 75 million units of blood are collected worldwide. Red blood cell (RBC) transfusion is one of the few treatments that adequately restore tissue oxygenation when oxygen demand exceeds supply. Although the respiratory function of blood has been studied intensively, the trigger for RBC transfusion remains controversial, and doctors rely primarily on clinical experience. Laboratory assays that indicate failing tissue oxygenation would be ideal to guide the need for transfusion, but none has proved easy, reproducible, and sensitive to regional tissue hypoxia. The clinical importance of the RBCs storage lesion (ie, the time-dependent metabolic, biochemical, and molecular changes that stored blood cells undergo) is poorly understood. RBCs can be filtered, washed, frozen, or irradiated for specific indications. Donor screening and testing have dramatically reduced infectious risks in the developed world, but infection remains a major hazard in developing countries, where 13 million units of blood are not tested for HIV or hepatitis viruses. Pathogen inactivation techniques are in clinical trials for RBCs, but none is available for use. Despite serious immunological and non-immunological complications, RBC transfusion holds a therapeutic index that exceeds that of many common medications.

Modi AA, Wright EC, Seeff LB. · The National Institute of Diabetes and Digestive and Kidney Diseases, The National Institute of Health, Bethesda, MD, USA. · Antivir Ther. · Pubmed #17591018 No free full text.

Abstract: Complementary and alternative medicine (CAM) has been used for centuries in China and Japan to treat various illnesses, including viral hepatitis. Several therapeutic approaches constitute CAM, the most relevant for this review being the use of herbals. However, profound disagreements exist between conventional and alternative medicine practitioners regarding their value. Western medical advocates cite deep concerns about the purity of most herbals because of lack of standardized production, the paucity of pharmacokinetic data, the fact that few well-designed randomized, controlled trials of these products have been performed and the evidence that some herbals have been responsible for severe adverse effects. Nevertheless, many in the public, even in western countries, turn to the use of herbals, believing that they must be safe and effective because they are 'natural' and have been used for centuries, and because of dissatisfaction with conventional medicine. Accordingly, their use in western countries and the costs incurred have increased each year. While there is evidence that some herbals have physiological effects, there still is insufficient evidence to recommend their use. This paper reviews the classification, epidemiology and philosophy of CAM, and the reasons advanced for herbal use to treat viral hepatitis. The criteria necessary to develop a potential pharmacological agent are presented, as well as the requirements for conducting a scientifically valid treatment trial of herbals. Five herbals used in the past to treat viral hepatitis are reviewed and evaluated for the quality of their studies and mention is made of herbals known to have adverse effects.

Noor A, Knox KS. · Division of Pulmonary and Critical Care Medicine, Indiana University and the Richard L. Roudebush VA Medical Center, Indianapolis, IN. · Clin Dermatol. · Pubmed #17560302 No free full text.

Abstract: The immunopathogenesis of sarcoidosis has been difficult to charaterize given the heterogeneity of disease, the elusiveness of the causative antigen, and the lack of an adequate animal model. However, by examining well-defined clinical cohorts, the interplay between genetic predisposition and immunologic response has been increasingly informative. Technological advances in cellular analysis have allowed researchers to characterize the immune responses important in the maintenance of granulomatous inflammation. Finally, "new" clinical observations such as granuloma responsiveness to targeted biological therapies, sarcoid developing during immune restoration, and the relationship between sarcoidosis and Hepatitis C will provide future insight to the immunopathogenesis of sarcoidosis.

Rehermann B. · Immunology Section, Liver Diseases Branch, NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland 20892, USA. · Semin Liver Dis. · Pubmed #17520515 No free full text.

Abstract: Chronic hepatitis B and C cause significant morbidity and mortality worldwide. Antiviral therapy suppresses but does not eliminate chronic hepatitis B virus (HBV) infection, and it is effective in only half of all hepatitis C virus (HCV)-infected patients. Because adaptive immune responses are associated with spontaneous resolution of acute HBV and HCV infection, therapeutic enhancement of immune responses has been proposed as alternative or supplementary therapy for chronic infection. However, all efforts have been hampered by poor proliferation and effector functions of HBV- and HCV-specific CD4 and CD8 T cells, which are thought to be due to T cell exhaustion, high antigenic load, and viral escape. Recent studies revealed that endogenous factors, such as regulatory T cells, immunosuppressive cytokines, and inhibitory receptors, also contribute to the impairment of virus-specific T cell responses in chronic infection, perhaps reflecting the host's attempt to protect itself against immune-mediated pathology. These endogenous mechanisms and potential avenues to revert them are the subject of this review.

Maher SG, Romero-Weaver AL, Scarzello AJ, Gamero AM. · Cancer and Inflammation Program, Laboratory of Experimental Immunology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702-1201, USA. · Curr Med Chem. · Pubmed #17504213 No free full text.

Abstract: Interferons (IFNs) are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumor, and immunomodulatory properties. While their complex mechanisms of action remain unclear, IFNs are used clinically in the treatment of viral infections, such as hepatitis B and hepatitis C, and remain the primary treatment for a limited number of malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma and in autoimmune diseases such as multiple sclerosis. IFNs not only regulate somatic cell growth and division but also influence cell survival through the modulation of apoptosis. Paradoxically, IFNs are described to be both pro- and anti-apoptotic in nature. The biological effects of IFNs are primarily mediated via activation of the JAK/STAT pathway, formation of the ISGF3 and STAT1:STAT1 protein complexes, and the subsequent induction of IFN-stimulated genes. However, the activation of JAK/STAT-independent signal transduction pathways also contribute to IFN-mediated responses. To further demonstrate the complexity of the downstream events following stimulation, oligonucleotide microarray studies have shown that in excess of 300 genes are induced following treatment with IFN, some of which are crucial to the induction of apoptosis and cell growth control. In this review we describe the recent advances made in elucidating the various signaling pathways that are activated by IFNs and how these diverse signals contribute to the regulation of cell growth and apoptosis and inhibition of viral replication. Furthermore, we highlight the role of specific signaling molecules and the function(s) of particular IFN-stimulated genes that have been implicated in determining cell fate in response to IFN, as well as the clinical experience of IFN immunotherapy.

Bryant BJ, Klein HG. · National Institutes of Health, Warren G. Magnuson Clinical Center, Department of Transfusion Medicine, 10 Center Dr, MSC-1184, Building 10, Room 1C711, Bethesda, MD 20894-1184, USA. · Arch Pathol Lab Med. · Pubmed #17488157 No free full text.

Abstract: CONTEXT: Pathogen inactivation provides a proactive approach to cleansing the blood supply. In the plasma fractionation and manufacturing industry, pathogen inactivation technologies have been successfully implemented resulting in no transmission of human immunodeficiency, hepatitis C, or hepatitis B viruses by US-licensed plasma derivatives since 1985. However, these technologies cannot be used to pathogen inactivate cellular blood components. Although current blood donor screening and disease testing has drastically reduced the incidence of transfusion-transmitted diseases, there still looms the threat to the blood supply of a new or reemerging pathogen. Of particular concern is the silent emergence of a new agent with a prolonged latent period in which asymptomatic infected carriers would donate and spread infection. OBJECTIVE: To review and summarize the principles, challenges, achievements, prospective technologies, and future goals of pathogen inactivation of the blood supply. DATA SOURCES: The current published English-language literature from 1968 through 2006 and a historical landmark article from 1943 are integrated into a review of this subject. CONCLUSIONS: The ultimate goal of pathogen inactivation is to maximally reduce the transmission of potential pathogens without significantly compromising the therapeutic efficacy of the cellular and protein constituents of blood. This must be accomplished without introducing toxicities into the blood supply and without causing neoantigen formation and subsequent antibody production. Several promising pathogen inactivation technologies are being developed and clinically tested, and others are currently in use. Pathogen inactivation offers additional layers of protection from infectious agents that threaten the blood supply and has the potential to impact the safety of blood transfusions worldwide.

Modi AA, Feld JJ. · Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1800, USA. · AIDS Rev. · Pubmed #17474311 No free full text.

Abstract: With increasing access to antiretroviral therapy across sub-Saharan Africa, progress is finally being made in combating the devastating HIV epidemic. As HIV-infected individuals live longer, the effects of coinfection with chronic hepatitis B and C will likely become an increasingly relevant issue. Indeed, HIV adversely affects the natural history of HBV and HCV, both of which are endemic across the African continent, Issues ranging from appropriate diagnostic testing to prevention and treatment are affected by HIV coinfection, particularly in resource-limited settings. In addition, some of the more complex problems such as occult infection, immune reconstitution, and antiretroviral hepatotoxicity are becoming increasingly important considerations. In this review, we present the available data on coinfection in Africa with a major emphasis on prevalence, routes of transmission, prevention and treatment strategies.

Ghany M, Liang TJ. · Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. · Gastroenterology. · Pubmed #17408658 No free full text.

Abstract: Chronic hepatitis B continues to be a major cause of end-stage liver disease and hepatocellular carcinoma worldwide. Nucleos(t)ide analogues have proven to be effective in controlling the disease and perhaps decreasing the incidence of hepatocellular carcinoma. However, development of drug resistance is a major limitation to their long-term effectiveness. Understanding the mechanisms of drug resistance are important for designing new agents and devising strategies to manage and prevent the development of antiviral drug resistance. The development of resistance is determined by an interplay of viral, host, and drug characteristics Homology of the HBV polymerase to the human immunodeficiency virus-1 reverse transcriptase has allowed predictions to be made on the effect mutations have on HBV polymerase structure. In vitro functional studies provide complementary information. Several broad principles on the mechanism of resistance have emerged from these studies. First, most of the primary mutations cluster in the vicinity of the incoming nucleotide and act by directly affecting the position or stability of the bound substrate, template, or primer. In contrast, secondary mutations tend to occur away from the nucleotide-binding pocket. Finally, the structural and functional consequences of mutations are quite variable among the different agents. This paper reviews the key mutations and mechanisms associated with resistance to the nucleos(t)ide analogues approved for clinical use and discuss new targets for drug development.