Hepatitis: London, EN

Mieli-Vergani G, Vergani D. · Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK. · World J Gastroenterol. · Pubmed #18528933 links to  free full text

Abstract: Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1) or liver kidney microsomal antibody (LKM1, type 2). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age, and commonly have partial IgA deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in both groups. The most common type of paediatric sclerosing cholangitis is ASC. The clinical, biochemical, immunological, and histological presentation of ASC is often indistinguishable from that of AIH type 1. In both, there are high IgG, non-organ specific autoantibodies, and interface hepatitis. Diagnosis is made by cholangiography. Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates, times to normalization of biochemical parameters, and decreased inflammatory activity on follow up liver biopsies. However, the cholangiopathy can progress. There may be evolution from AIH to ASC over the years, despite treatment. De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH, including elevated titres of serum antibodies, hypergammaglobulinaemia, and histological findings of interface hepatitis, bridging fibrosis, and collapse. Like classical AIH, it responds to treatment with prednisolone and azathioprine. De novo AIH post liver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection. Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to the development of autoimmune phenomena is unclear. Whatever its etiology, the recognition of this potentially life-threatening syndrome is important since its management differs from that of standard anti-rejection therapy.

Vergani D, Mieli-Vergani G. · Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. · World J Gastroenterol. · Pubmed #18528928 links to  free full text

Abstract: The histological hallmark of autoimmune hepatitis (AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes, macrophages, and plasma cells. An unknown but powerful stimulus must be promoting the formation of this massive inflammatory cellular reaction that is likely to initiate and perpetuate liver damage. An autoimmune attack can follow different pathways to inflict damage on hepatocytes. Liver damage is likely to be orchestrated by CD4(+) T lymphocytes recognizing an autoantigenic liver peptide. To trigger an autoimmune response, the peptide must be embraced by an HLA class II molecule and presented to naive CD4(+) T helper (Th0) cells by professional antigen presenting cells, with the co-stimulation of ligand-ligand fostering interaction between the two cells. Th0 cells become activated, differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen, and initiate a cascade of immune reactions determined by the cytokines produced by the activated T cells. Th1 cells, arising in the presence of the macrophage-derived interleukin (IL) -12, secrete mainly IL-2 and interferon-gamma (IFN-gamma), which activate macrophages, enhance expression of HLA class I (increasing liver cell vulnerability to a CD8(+) T cell cytotoxic attack), and induce expression of HLA class II molecules on hepatocytes. Th2 cells, which differentiate from Th0 if the microenvironment is rich in IL-4, produce mainly IL-4, IL-10, and IL-13 which favour autoantibody production by B lymphocytes. Physiologically, Th1 and Th2 antagonize each other. Th17 cells, a recently described population, arise in the presence of transforming growth factor beta (TGF-beta) and IL-6 and appear to have an important effector role in inflammation and autoimmunity. The process of autoantigen recognition is strictly controlled by regulatory mechanisms, such as those exerted by CD4(+)CD25(+) regulatory T cells, which derive from Th0 in the presence of TGF-beta, but in the absence of IL-6. If regulatory mechanisms fail, the autoimmune attack is perpetuated. Over the past three decades different aspects of the above pathogenic scenario have been investigated. In particular, a defect in immunoregulation affecting CD4(+)CD25(+) regulatory T cells (T-regs) has been demonstrated in AIH, particularly at diagnosis or during relapse. Advances in the study of autoreactive T cells have occurred mostly in AIH type 2, since the knowledge that CYP2D6 is the main autoantigen has enabled the characterization of both CD4 and CD8 T cells targeting this cytochrome. CD4 T cells from patients with type 2 AIH positive for the predisposing HLA allele DRB1*0701 recognize seven regions of CYP2D6, five of which are also recognized by CD8 T cells. High numbers of IFN-gamma producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage, suggesting a combined cellular immune attack.

Morris MA, Young LS, Dawson CW. · Cancer Research (UK) Institute for Cancer Studies, The Medical School, University of Birmingham, Birmingham B15 2TT, UK. · Eur J Cell Biol. · Pubmed #18468721 No free full text.

Abstract: Approximately 15-20% of global cancer incidence is causally linked to viral infection, yet the low incidence of cancers in healthy infected individuals suggests that malignant conversion of virus-infected cells occurs after a long period as a result of additional genetic modifications. There are four families of viruses that are now documented to be involved in the development of human cancers which include members of the polyomavirus, hepadnavirus, papillomavirus and herpesvirus families. Although a number of these viruses are implicated in the aetiology of lymphomas or leukaemias, the vast majority are associated with malignancies of epithelial cells. In epithelial tissues, several classes of proteins are involved in maintaining tissue architecture, including those that promote cell-cell adhesion, and others, which mediate cell-matrix interactions. Proteins representative of all classes are frequently altered in malignant tumour cells that possess invasive and metastatic properties. Malignant tumour cells acquire mechanisms to degrade basement membranes and invade the underlying tissue. Many viruses encode proteins which engage signalling pathways that affect one or more of these mechanisms. It is believed that activation of these processes by chronic viral infection can, under certain circumstances, promote tumour cell invasion and metastasis. This review will take a brief look at the current knowledge of viral-induced alterations in cell motility and invasiveness in the context of tumour invasion and metastasis.

Thomson EC, Main J. · Department of Hepatology, Faculty of Medicine, Imperial College at St Mary's Hospital, London, UK. · J Viral Hepat. · Pubmed #18435718 No free full text.

Abstract: Many individuals are infected with both HIV and hepatitis C virus (HCV) infection. More rapid progression of liver disease is seen, higher levels of HCV RNA encourage transmission and sustained virological responses are lower in coinfected patients. The management of these patients is further complicated by potential interactions between antiretroviral therapy and peginterferon and ribavirin.

Dusheiko G, Nelson D, Reddy KR. · Royal Free Hospital, London, United Kingdom. · Antivir Ther. · Pubmed #18432160 No free full text.

Abstract: Ribavirin is a guanosine analogue that has little antiviral activity when used alone, but considerably enhances the efficacy of conventional and pegylated interferon in the treatment of hepatitis C virus (HCV). The precise mode of action of ribavirin is not fully understood; however, it is crucial for the achievement of high sustained virological response (SVR) rates by enhancing virological response and reducing relapse rates. Data from several studies have confirmed that higher initial doses of ribavirin lead to higher SVR rates. Furthermore, intensified ribavirin dosing might also improve SVR rates in 'difficult-to-cure' patients. It is also important to minimize ribavirin dose reductions to promote high SVR rates and to maintain ribavirin levels throughout treatment to prevent viral breakthrough and relapse. The pharmacokinetic profile of ribavirin reveals a long elimination half-life due to accumulation in the blood, such that its side-effect profile includes haemolytic anaemia. Therefore, finding the optimal ribavirin dose requires a balance between efficacy and its associated side effects to ensure improved patient outcomes. Here, we discuss how optimizing the ribavirin component of combined therapy for HCV is an essential part of treatment optimization.

Foster G, Mathurin P. · Queen Mary Hospital, University of London, London, UK. · Antivir Ther. · Pubmed #18432157 No free full text.

Abstract: Chronic hepatitis C is a major contributor to cirrhosis and hepatocellular cancer worldwide, justifying the considerable research effort aimed at understanding the disease and refining its treatment. As a result, significant therapeutic advances have been made in the last decade, particularly with regard to the development of pegylated interferons and ribavirin. This review will discuss the physical properties, pharmacokinetics, viral kinetics and side-effect profiles of the different treatment options and how they have improved, culminating in the use of pegylated interferon and ribavirin combination therapy as the current standard of care.

Cross TJ, Antoniades CG, Harrison PM. · Institute of Liver Studies, King's College Hospital, London, UK. · Postgrad Med J. · Pubmed #18424572 No free full text.

Abstract: Current treatment for patients with chronic hepatitis C virus (HCV) infection consists of the combination of pegylated interferon and ribavirin. This treatment regimen achieves a sustained virological response, defined as undetectable HCV RNA 6 months after treatment cessation, in 50% of patients overall. There is therefore a need for new treatments to improve the sustained virological response rate and reduce the number of adverse effects associated with pegylated interferon and ribavirin. This review examines the current management of chronic HCV infection, including who is eligible for treatment, the optimum duration of treatment, and management of side effects. New drugs in development, such as HCV-specific protease inhibitors, polymerase inhibitors, immune modulators and ribavirin analogues, are outlined, and their role in the treatment armamentarium is discussed, whether used alone or in combination with existing treatments.

Williams R. · Institute of Hepatology, University College London Medical School, 69-75 Chenies Mews, London, WC1E 6HX, UK. · Alcohol Alcohol. · Pubmed #18385413 links to  free full text

Abstract: Rising levels of alcohol consumption in the UK are leading to substantial increases in morbidity and mortality from liver disease. Drinking is starting at an earlier age with binging an increasing common pattern, and women are overtaking men in the consumption. Manifestations of liver damage range from fatty liver to end-stage cirrhosis, but it is the increasing number of cases presenting with an acute alcoholic hepatitis (AAH) that are the cause for greatest concern. Development of well-validated prognostic scoring systems (Maddrey Modified Discriminant Function, Glasgow Alcohol Score) makes it possible to select those patients with AAH who are most likely to respond to corticosteroids. The results of early pilot studies of a number of anti-TNF agents are encouraging and with infliximab, reduction in portal pressure has been demonstrated to be consequent on controlling inflammatory processes in the liver. For those deteriorating to the stage of liver failure, artificial liver support with MARS is of value in correcting major pathophysiological disturbances and as a bridge to liver transplantation, the results of which both for end-stage alcoholic cirrhosis and for AAH--of which there is limited experience, are excellent. Even as the stringent regulatory measures needed to control rising alcohol consumption are introduced by government, the burden of liver disease in the UK will remain high for years to come.

MacDonald DC, Nelson M, Bower M, Powles T. · Chelsea and Westminster hospital, London, United Kingdom. · World J Gastroenterol. · Pubmed #18350596 links to  free full text

Abstract: The incidence of hepatocellular carcinoma (HCC) in patients with human immunodeficiency virus (HIV) is rising. HCC in HIV almost invariably occurs in the context of hepatitis C virus (HCV) or hepatitis B virus (HBV) co-infection and, on account of shared modes of transmission, this occurs in more than 33% and 10% of patients with HIV worldwide respectively. It has yet to be clearly established whether HIV directly accelerates HCC pathogenesis or whether the rising incidence is an epiphenomenon of the highly active antiretroviral therapy (HAART) era, wherein the increased longevity of patients with HIV allows long-term complications of viral hepatitis and cirrhosis to develop. Answering this question will have implications for HCC surveillance and the timing of HCV/HBV therapy, which in HIV co-infection presents unique challenges. Once HCC develops, there is growing evidence that HIV co-infection should not preclude conventional therapeutic strategies, including liver transplantation.

Vergani D, Mieli-Vergani G. · Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London SE5 9RS, UK. · Clin Liver Dis. · Pubmed #18242504 No free full text.

Abstract: This article describes the connection between autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). The two conditions have chronicity, liver inflammation, and a positive autoimmune serology in common; they differ in terms of gender distribution and bile duct damage. There is evidence suggesting that AIH and PSC are immune-mediated diseases. PSC and AIH could lie within the spectrum of the same disease process. Future studies should determine how frequently AIH evolves to PSC.

Kass GE, Price SC. · Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, UK. · Clin Liver Dis. · Pubmed #18242496 No free full text.

Abstract: Mitochondria have multiple functions in eukaryotic cells and are organized into dynamic tubular networks that continuously undergo changes through coordinated fusion and fission and migration through the cytosol. Mitochondria integrate cell-signaling networks, especially those involving the intracellular messenger Ca(2+), into the regulation of metabolic pathways. Recently, it has become clear that mitochondria are central to the three main cell death pathways, namely necrosis, apoptosis, and autophagic cell death. This article discusses the role of mitochondria in drug-induced cholestatic injury to the liver. The role of mitochondria in the cellular adaptation against the toxic effects of bile acids is discussed also.

Newland A. · Department of Haematology, The Royal London Hospital, London, UK. · Eur J Haematol Suppl. · Pubmed #18211570 No free full text.

Abstract: Immune thrombocytopenic purpura (ITP) is a fairly common hematological disorder and is a minor disease for many affected patients; most are in good health, and many can tolerate low platelet counts without the need for treatment. For the majority of patients who do undergo treatment, first-line therapies, including corticosteroids, are effective in increasing platelet counts, although long-term use can be associated with adverse effects. Second-line therapies, such as immunosuppressants, have been largely untested in controlled studies of ITP patients. Like first-line therapies, splenectomy is effective for many patients; however, it is frequently avoided by physicians who prefer the use of alternative drug therapies due to concerns about safety risks and is often declined by patients reluctant to undergo surgery. Thus, approaches to avoid or defer the use of splenectomy have been actively pursued. An anti-CD20 antibody, rituximab, can limit the production of autoantibodies, but reactivated viral infections have been reported with its use. Agents that directly stimulate platelet production, such as thrombopoietin (TPO) receptor-binding agents, have shown promise in clinical trials of ITP patients as well as in hepatitis C virus-infected individuals with thrombocytopenia. Two TPO receptor agonists in advanced clinical development--eltrombopag and AMG 531--are discussed here. Both eltrombopag and AMG 531 appear to be effective in raising platelet counts and both have been well tolerated in clinical trials to date. However, potential safety issues with thrombopoietic growth factors include thrombocytosis, rebound thrombocytopenia, and increased bone marrow fibrosis. Further testing will determine which safety issues--if any--are of clinical concern.

Saich R, Chapman R. · The Department of Gastroenterology, The John Radcliffe Hospital, Headley Way, Headington, Oxford, Oxfordshire, United Kingdom. · World J Gastroenterol. · Pubmed #18200656 links to  free full text

Abstract: Primary sclerosing cholangitis (PSC) is a chronic progressive disorder of unknown aetiology characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include itch and lethargy and in advanced cases cholangitis and end-stage liver disease, however increasing numbers of asymptomatic individuals are being identified. The disease is rare in the general population but is strongly associated with inflammatory bowel disease (IBD) affecting up to 5% of patients with ulcerative colitis, with a slightly lower prevalence (up to 3.6%) in Crohn's disease. The strength of this association means that the vast majority (> 90%) of patients with PSC also have IBD, although many may have only mild gastro-intestinal symptoms. Usually IBD presents before PSC, although vice-versa can occur and the onset of both conditions can be separated in some cases by many years. Mean age of diagnosis of PSC is in the fifth decade of life with a strong male predominance. Risk is increased in those with a family history of PSC, suggesting a genetic predisposition and the disease is almost exclusive to non-smokers. The ulcerative colitis associated with PSC is characteristically mild, runs a quiescent course, is associated with rectal sparing, more severe right sided disease, backwash ileitis and has a high risk of pouchitis post-colectomy. Most worrisome is the high risk of colorectal malignancy which necessitates routine colonoscopic surveillance. Cholangiocarcinoma is also a frequent complication of PSC with a 10%-15% lifetime risk of developing this condition. Treatment with high dose ursodeoxycholic acid offers some chemoprotective effects against colorectal malignancy and may decrease symptoms, biochemical and histological progression of liver disease. Small duct PSC patients characteristically have normal cholangiography, and liver biopsy is required for diagnosis, it appears to have a more favourable prognosis. Autoimmune Hepatitis (AIH) is also more prevalent in patients with IBD, with up to 16% of patients with AIH also having ulcerative colitis. A small subgroup of patients have a AIH-PSC overlap syndrome and the management of these patients depends on liver histology, serum IgM levels, autoantibodies, degree of biochemical cholestasis and cholangiography as some of these patients may respond to immunosuppression.

Prentice AM, Darboe MK. · MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London, UK. · Nestle Nutr Workshop Ser Pediatr Program. · Pubmed #18196953 No free full text.

Abstract: Differing trajectories of infant and child growth are associated with different patterns of disease and mortality in adulthood. Since postnatal growth patterns are partially modifiable by diet, these associations raise fresh questions about what constitutes an optimal growth rate. We use data from contemporary societies that still suffer poor nutrition and high burdens of infectious disease to illustrate early growth patterns that have likely been typical of our evolutionary past. Pathogenic assault is a major suppressor of growth; populations frequently average -1.0 to -1.5 z scores (standard deviations relative to standard growth curves) for height, and -2.0 to -2.5 z scores for weight, body mass index and head circumference. Many infections are symptomatic (e.g. diarrhea, malaria, pneumonia, HIV), but others are subclinical (e.g. hepatitis B, cytomegalovirus, Epstein-Barr virus, herpes, Helicobacter pylori). The great majority of young children become infected by multiple pathogens which initiate a downward cycle of infection --> suppressed appetite and malabsorption --> reduced growth --> lowered immunity --> repeated infection. Examination of the evolutionary 'norm' for early growth, and the external environmental factors that influenced it, may provide clues towards identifying the current day optimum for growth.

Newland A. · Department of Haematology, Centre for Haematology, The Royal London Hospital, London, UK. · Semin Hematol. · Pubmed #18096471 No free full text.

Abstract: Thrombopoietin (TPO) is a potent endogenous cytokine and the principal regulator of platelet production. Advances in the understanding of the structure of TPO enabled development of the first generation of thrombopoietic growth factors, recombinant human thrombopoietin (rhTPO) and pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF). Clinical results showed that these agents were effective in promoting increases in platelet counts in a variety of thrombocytopenic disorders. However, clinical development was halted when studies demonstrated risk for autoantibody formation with cross-reactivity to endogenous TPO. A second generation of thrombopoietic growth factors, including TPO peptide and nonpeptide mimetics and TPO agonist antibodies, utilizing different mechanisms from recombinant growth factors to promote platelet production, are currently in development. The TPO peptide mimetic AMG 531 and the nonpeptide mimetic eltrombopag are in advanced clinical trials and have both resulted in dose-dependent increases in platelets in healthy subjects and in significant increases in platelets in patients with chronic immune thrombocytopenic purpura (ITP). Clinical trials are also being conducted to examine the efficacy and safety of eltrombopag to treat thrombocytopenia in hepatitis C virus (HCV)-infected individuals. These agents appear to be well tolerated and the formation of autoantibodies appears to be limited to first-generation growth factors. Increases in marrow reticulin have been demonstrated with some growth factors, but this appears to be a reversible phenomenon and is not associated with formation of collagen fibrosis. There appears to be no increased incidence of thrombotic events in patients who achieve high platelet counts with growth factor treatments, and although occasional thrombotic events have been reported, their association to the treatment is uncertain. While there is evidence that activation of signaling pathways involved in platelet production may result in reduction in the threshold for platelet activation, this appears to have minimal clinical relevance for the use of thrombopoietin growth factors.

Matutes E, Oscier D, Montalban C, Berger F, Callet-Bauchu E, Dogan A, Felman P, Franco V, Iannitto E, Mollejo M, Papadaki T, Remstein ED, Salar A, Solé F, Stamatopoulos K, Thieblemont C, Traverse-Glehen A, Wotherspoon A, Coiffier B, Piris MA. · Section of Haemato-Oncology, Institute of Cancer Research, London, UK. · Leukemia. · Pubmed #18094718 No free full text.

Abstract: Since the initial description of splenic marginal zone lymphoma (SMZL) in 1992, an increasing number of publications have dealt with multiple aspects of SMZL diagnosis, molecular pathogenesis and treatment. This process has identified multiple inconsistencies in the diagnostic criteria and lack of clear guidelines for the staging and treatment. The authors of this review have held several meetings and exchanged series of cases with the objective of agreeing on the main diagnostic, staging and therapeutic guidelines for patients with this condition. Specific working groups were created for diagnostic criteria, immunophenotype, staging and treatment. As results of this work, guidelines are proposed for diagnosis, differential diagnosis, staging, prognostic factors, treatment and response criteria. The guidelines proposed here are intended to contribute to the standardization of the diagnosis and treatment of these patients, and should facilitate the future development of clinical trials that could define more precisely predictive markers for histological progression or lack of response, and evaluate new drugs or treatments.

Aceijas C, Rhodes T. · Centre for Research on Drugs and Health Behaviour, London School of Hygiene and Tropical Medicine, University of London, London, UK. <> · Int J Drug Policy. · Pubmed #17854722 No free full text.

Abstract: OBJECTIVE: In this paper, we review evidence of HCV prevalence among injecting drug users (IDUs) worldwide. METHODS: We undertook a desk-based review of both 'grey' and published literature released between 1998 and 2005. RESULTS: Data on HCV prevalence among IDUs was found in 57 countries and in 152 sub-national areas. We found reports of HCV prevalence of at least 50% among IDUs in 49 countries or territories. Available regional estimates varied widely, from 10 to 96% in Eastern Europe and Central Asia, from 10 to 100% in South and South-East Asia, from 34 to 93% in East-Asia and the Pacific, from 5 to 60% in North Africa and the Middle-East, from 2 to 100% in Latin America, from 8 to 90% in North America, from 25 to 88% in Australia and New Zealand, and from 2 to 93% in Western Europe. Only in Colombia and Lebanon were all HCV prevalence estimates below 20%. In addition, evidence of HIV/HCV co-infection among IDUs was found in 16 countries. In China, Poland, Puerto Rico, Russia, Spain, Switzerland, Thailand and Viet Nam, estimates of the prevalence of HIV/HCV co-infection among IDUs reached 90%. DISCUSSION: Taken together, data suggest high global prevalence of HCV and HIV/HCV co-infection among IDUs. We suggest exploring protective factors in sites of low HCV prevalence.

Scully C, Carrozzo M. · University College London, Eastman Dental Institute, UK. · Br J Oral Maxillofac Surg. · Pubmed #17822813 No free full text.

Abstract: Lichen planus (LP) is a common disorder in which auto-cytotoxic T lymphocytes trigger apoptosis of epithelial cells leading to chronic inflammation. Oral LP (OLP) can be a source of severe morbidity and has a small potential to be malignant. The diagnosis of OLP can be made from the clinical features if they are sufficiently characteristic, particularly if typical skin or other lesions are present, but biopsy is recommended to confirm the diagnosis and to exclude dysplasia and malignancy. OLP is treated with anti-inflammatory agents, mainly the topical corticosteroids, but newer agents and techniques are becoming available.

Dusheiko G, Danta M. · UCL Institute of Hepatology and Royal Free Hospital, London, UK. · Drugs Today (Barc). · Pubmed #17724496 No free full text.

Abstract: The hepatitis B virus (HBV) has a complex natural history and causes a wide spectrum of disease. Choices of therapy depend on a number of factors predictive of treatment response, clinical circumstances and stage of disease, and the likelihood and consequences of resistance to treatment. Telbivudine (beta-L-2'deoxythymidine) is a thymidine analogue that belongs to a new class of beta-L-configuration nucleoside analogues with specific activity against hepadnavirus. Phase III studies of telbivudine versus lamivudine in hepatitis B e antigen (HBeAg) and anti-HBe have been completed. In HBeAg-positive patients, HBV DNA was not detectable by polymerase chain reaction (PCR) assay in 56% of the HBeAg-positive patients receiving telbivudine after two years of treatment. In HBeAg-negative patients, at two years, HBV DNA was undetectable by PCR in 82% of HBeAg-negative patients (versus 52% of lamivudine recipients). Patients who were PCR-negative after 24 weeks were less likely to develop resistance. HBeAg seroconversion rates were also greatest in patients whose HBV DNA was undetectable at 24 weeks. These results are promising and could be used to devise a strategy to utilize combination therapy or to adjust therapy if an inadequate early viral response is observed. However, resistance is a potential shortcoming of the use of single agents for the treatment of HBV.

Thomas T, Foster G. · University College London Hospital NHS Trust, London. · Int J Nanomedicine. · Pubmed #17722508 links to  free full text

Abstract: Nanotechnology is the application of nanotechnology within medicine. An illustration of this is the use of pegylation as a means of modifying naturally occurring proteins which may have clinical applications, in order to improve the pharmacodynamics of the protein resulting in an effective medication. An example of this is pegylated interferon. The purpose of this review is to examine the chemistry, clinical pharmacology, pharmacokinetics, pharmacodynamics, and clinical studies with 40 kDa pegylated interferon to illustrate the general principles of pegylated biological proteins. The use in clinical practice is reviewed along with the evidence for both efficiacy, safety, and advantages over standard interferon.

Crowther RA. · Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. · Philos Trans R Soc Lond B Biol Sci. · Pubmed #17690055 links to  free full text

Abstract: The electron microscope provides a powerful tool for investigating the structure of biological complexes such as viruses. A modern instrument is fully capable of atomic resolution on suitable non-biological specimens, but biological materials are difficult to preserve, owing to their fragility, and to image, owing to their radiation, sensitivity. The act of imaging the specimen severely damages it. Originally, samples were prepared by staining with a heavy metal salt, which provides a stable specimen but limits the amount of details that can be retrieved. Now particulate specimens, such as viruses, are prepared by rapid freezing of unstained material and observed in a frozen state with low doses of electrons. The resulting images require extensive computer processing to extract fully detailed three-dimensional information about the specimen. The whole process is referred to as single-particle electron cryomicroscopy. Using this approach, the structure of the human hepatitis B virus core was solved at the level of the protein fold. By comparing maps of RNA- and DNA-containing cores, it was possible to propose a model for the maturation and control of the envelopment of the virus during assembly. These examples show that cryomicroscopy offers great potential for understanding the structure and function of complex biological assemblies.

Matutes E. · Haemato-Oncology Unit, Royal Marsden Hospital and Institute of Cancer Research, 203 Fulham Road, London, SW3 6JJ, UK. · Curr Treat Options Oncol. · Pubmed #17680218 No free full text.

Abstract: Splenic marginal zone lymphoma with or without villous lymphocytes (SLVL/SMZL) is a low grade B-cell lymphoma that affects patients in the sixth decade and has a median survival greater than 10 years. A substantial proportion of patients die from causes unrelated to the disease. Close to a third of the patients do not require intervention and a policy of watch and see is reasonable and recommended. There are several therapeutic options that have proved effective in these patients. Due to the natural history of the lymphoma, the main goal of all these treatments is to achieve control of the disease rather than its eradication. Retrospective designs of all documented studies, the lack of uniform response criteria and the heterogeneity in the patient's features makes interpretation of the data difficult. Splenectomy remains one of the first line options in patients fit for surgery. Amongst chemotherapy, purine analogues, in particular fludarabine in combination or not with Rituximab and Rituximab alone have a greater efficacy than alkylating agents in terms of achieving better quality of response and longer progression free survival; therefore these agents are recommended particularly in patients who are not candidates for surgery or relapse after splenectomy. In the small proportion of patients with concomitant hepatitis C virus (HCV) infection, Interferon-alpha, ribavirin or a combination of both has demonstrated a significant activity with responses correlating with clearance of HCV RNA in the blood; therefore, these agents should be considered in the therapeutic scenario as a first line in these small cohort of patients. Patients that transform to high-grade lymphoma and the minority that have TP53 abnormalities should be treated with other schedules. Prospective randomized trials would be desirable to ascertain the independent prognostic factors and the biological features that predict disease progression and drug resistance to device the optimal management and treatment for SLVL/SMZL.

Hodgetts A, Levin M, Kroll JS, Langford PR. · Imperial College London, Department of Paediatrics, Division of Medicine, St Mary's Campus, London, UK. · Future Microbiol. · Pubmed #17661674 No free full text.

Abstract: Surface enhanced laser desorption ionization-time of flight is a mass spectrometric-based method that requires a minimal amount of sample for analysis and can be used for high-throughput screening. It has been used to discover serum or tissue protein signatures and biomarkers for infectious diseases in the fields of virology (hepatitis B and C viruses, severe acute respiratory syndrome, HIV-1, human T-cell leukemia virus-1 and BK virus), parasitology (trypanosomiasis) and bacteriology (intra-amniotic inflammation, tuberculosis and bacterial endocarditis). The protein signatures, or biomarkers, can be used to diagnose infection, predict disease states and to inform on disease processes. Careful attention to experimental design, sample handling and storage, and the use of appropriate internal controls is crucial to success.

Low E, Nelson M. · Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. · J HIV Ther. · Pubmed #17589390 No free full text.

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Clements AC, Pfeiffer DU, Martin V, Otte MJ. · Epidemiology Division, Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hatfield, Hertfordshire, United Kingdom. · Prev Vet Med. · Pubmed #17570545 No free full text.

Abstract: Rift Valley fever (RVF) epidemics have serious consequences for human and animal health and the livestock trade. Recent epidemics have occurred in previously unaffected regions, increasing concerns that the geographical range of RVF will continue to expand. We conducted an extensive, systematic review of the literature to obtain serological data for RVF in Africa, collected between 1970 and 2000 from human, livestock and wild ungulate populations. Aims were to calculate sub-national estimates of RVF infection prevalence and to define areas where no information was available. We presented the data (aggregated at the first administrative level of countries) using a geographical information system. Data from 71 publications were used to build a spatially explicit Bayesian logistic-regression model, with spatial and non-spatial random effects, allowing us to identify clusters of high and low RVF seroprevalence, and fixed effects that described the disparate nature of the survey subjects and methods. Significant high-prevalence clusters encompassed areas that had experienced epidemics during the late 20th century and significant low-prevalence clusters were located in contiguous areas of Western and Central Africa.