International Journal of Medical Sciences

Characterization of N200 and P300: Selected Studies of the Event-Related Potential

Salil H. Patel, Pierre N. Azzam — 2005-10-1

The Event-Related Potential (ERP) is a time-locked measure of electrical activity of the cerebral surface representing a distinct phase of cortical processing. Two components of the ERP which bear special importance to stimulus evaluation, selective attention, and conscious discrimination in humans are the P300 positivity and N200 negativity, appearing 300 ms and 200 ms post-stimulus, respectively. With the rapid proliferation of high-density EEG methods, and interdisciplinary interest in its application as a prognostic, diagnostic, and investigative tool, an understanding of the underpinnings of P300 and N200 physiology may support its application to both the basic neuroscience and clinical medical settings. The authors present a synthesis of current understanding of these two deflections in both normal and pathological states.

Enhanced surveillance for childhood hepatitis B virus infection in Canada, 1999-2003

2005-10-1

Since hepatitis B virus (HBV) infection can have serious sequelae, especially if infection occurs during childhood, there is a continuing need to examine its epidemiology so as to inform control measures. We analyzed trends in disease incidence and patterns of hepatitis B virus (HBV) transmission in both Canadian-born and non-Canadian-born children from 1999 to 2003, through the Enhanced Hepatitis Strain Surveillance System. Amongst Canadian-born children, the incidence of newly identified HBV infection per 100,000 declined significantly during the study period from 1.4 in 1999, to 0.5 in 2003 (RR, 0.75 per year; 95% CI, 0.60-0.95). Amongst non-Canadian-born children, the incidence of HBV infection per 100,000 ranged from 9.4 to 16.3, during the study period (linear trend test, p=0.69). Poisson regression analysis revealed that non-Canadian-born children were more likely to have HBV infection (RR, 12.3; 95% CI, 7.6 to 19.8), than Canadian-born children. HBV infection was found to be more common among children emigrating from high endemic area, than among Canadian-born children. Current Canadian immunization policy should take into consideration the protection of all children against HBV infection, including those coming from countries where mass hepatitis B vaccination programs have still not been launched.

Evaluation of maternal infusion therapy during pregnancy for fetal development

Dóra Petik, Erzsébet Puhó, Andrew E. Czeizel — 2005-10-1

The aim of this project was to study the possible association between maternal infusion treatments during pregnancy and variables of fetal development as well as the occurrence of congenital abnormalities (CA) in a case-control design. The large population-based data set of the Hungarian Case‑Control Surveillance of Congenital Abnormalities (HCCSCA) was evaluated based on the medically recorded infusion treatment during pregnancy. Of 22,843 case pregnant women who had newborns or fetuses with congenital abnormalities, 112 (0.5%), while of 38,151 control pregnant women who had newborn infants without any defects, 262 (0.7%), had infusion treatment during pregnancy. Infusion treatment was more frequent in the control group than in the case group with congenital abnormalities (adjusted POR with 945 95% CI: 0.7, 0.6-0.9) and there was no higher rate of maternal infusion treatments in any congenital abnormality group. Mean gestational age was shorter and mean birth weight was smaller in control newborn infants without CA born to mothers with infusion treatment during pregnancy than in the babies of mothers without infusion treatment. The prevalence of mild intrauterine growth retardation was more frequent in the fetuses of pregnant women with hyperemesis gravidarum treated with infusion. The results of the study suggest that infusion treatment of pregnant women did not associate with a higher risk of congenital abnormalities. In addition, the intravenous infusion of drugs has some, but limited efficacy to prevent the adverse effects of hyperemesis gravidarum and threatened preterm delivery.

A comparative analysis of antibody repertoire against Staphylococcus aureus antigens in Patients with Deep-Seated versus Superficial staphylococcal Infections

Ashok Kumar, Pallab Ray, Mamta Kanwar, Meera Sharma, Subhash Varma — 2005-10-1

Immunoblot and an enzyme-linked immunosorbent assays were used to evaluate and compare IgG antibodies against S. aureus whole cell lysate, cell wall peptidoglycan and lipoteichoic acid to discriminate between deep-seated and superficial S. aureus infection. Serum samples were examined from patients with deep-seated (n = 25) and superficial (n = 25) S. aureus infections and 15 healthy controls. Patients with deep-seated infections exhibited a large number of immuno-reactive bands in their IgG immunoblot profile as compared to those with superficial infections and healthy controls. Anti-staphylococcal IgG antibodies that reacted with two antigens of apparent molecular weight 110 and 98 kDa were specifically present in 96% (24/25) of patients with deep-seated infections, and were absent in, superficial and control sera. Moreover other Gram-positive and Gram-negative bacteria did not share these two unique antigens. The ELISA assays revealed significantly elevated levels of IgG antibodies to peptidoglycan (PG) in 18 of 25 (72%) patients with deep infection and 15 of 25 (60%) patients with superficial staphylococcal infection. The elevated levels of IgG antibodies to teichoic acid (TA) antigen were detected in all (100%) deep-seated group patients and among 40% (10/25) patients with superficial infection. An increase in levels of antibodies to PG showed a positive correlation trend with levels of IgG antibodies to TA only in deep infection group. Thus immunoblot detection of these two unique antigens as well as detection of elevated antibodies against PG and TA may be useful for the discrimination of staphylococcal deep-seated and superficial infection in humans.

Differential gene expression in HIV/SIV-associated and spontaneous lymphomas

2005-10-1

Diffuse large B-cell lymphoma (DLBCL) is more prevalent and more often fatal in HIV-infected patients and SIV-infected monkeys compared to immune-competent individuals. Molecular, biological, and immunological data indicate that virus-associated lymphomagenesis is similar in both infected hosts. To find genes specifically overexpressed in HIV/SIV-associated and non-HIV/SIV-associated DLBCL we compared gene expression profiles of HIV/SIV-related and non-HIV-related lymphomas using subtractive hybridization and Northern blot analysis. Our experimental approach allowed us to detect two genes (a-myb and pub) upregulated solely in HIV/SIV-associated DLBCLs potentially involved in virus-specific lymphomagenesis in human and monkey. Downregulation of the pub gene was observed in all non-HIV-associated lymphomas investigated. In addition, we have found genes upregulated in both non-HIV- and HIV-associated lymphomas. Among those were genes both with known (set, ND4, SMG-1) and unknown functions. In summary, we have demonstrated that simultaneous transcriptional upregulation of at least two genes (a-myb and pub) was specific for AIDS-associated lymphomas.

Application of Small Angle X-ray Scattering (SAXS) for Differentiation between Normal and Cancerous Breast Tissue

2005-7-5

Introduction: Small angle, between 3^° and 10^°, X ray scattering is predominantly coherent giving rise to diffraction effects that can be observed as constructive and destructive interferences. These interferences carry information about the molecular structure of the tissue and hence can be used to identify changes that occur due to cancer.

Method: In this study an energy dispersive X-ray diffraction method was used. The optimum scattering angle, determined from a series of measurements on adipose breast tissue at several angles from 4 to 7.3 degrees, was found to be 6.5^°. Once optimized the system was used to measure the diffraction profiles (corrected scattered intensity versus momentum transfer) of a total of 99 breast tissue samples. The samples were both normal and tumour samples.

Results: Adipose tissue showed a sharp, high intensity peak at low momentum transfer values of approximately 1.1nm-1. Adipose tissue, mixed tissue (adipose & fibroglandular) and tumor have peaks at different values of momentum transfer that can be used to identify the tissue. Benign and malignant breast tissues can also be differentiated by both peak positions and peak heights. It was also observed that the results were reproducible even after the tissue had been preserved at liquid nitrogen temperatures.

Conclusion: We were able to differentiate between normal, benign and malignant breast tissues by using energy dispersive small angle x-ray scattering.

Identification of Cellular Membrane Proteins Interacting with Hepatitis B Surface Antigen using Yeast Split-Ubiquitin System

2005-7-5

Hepatitis B surface antigen (HBsAg) is the major component of the envelope of hepatitis B virus (HBV). As a resident membrane protein in the endoplasmic reticulum, it plays a key role in the viral morphogenesis. Little is known about cellular proteins that interact with HBsAg and thereby contributing to HBV morphogenesis. Using the yeast split-ubiquitin system, a number of cellular membrane proteins have been isolated in this study. These include a resident protein of endoplasmic reticulum (thioredoxin-related transmembrane protein 2), an adaptor protein involved in clathrin-mediated endocytosis and HIV-mediated downregulation of CD4, and a co-receptor of coxsakie B virus. The significance of our findings is suggested by the identification of cellular membrane proteins interacting with other virus proteins. Further functional analysis of these HBsAg- interacting cellular membrane proteins should shed new insights on their role in HBV morphogenesis.

Potassium Deposition During And After Hypokinesia In Potassium Supplemented And Unsupplemented Rats

Yan G. Zorbas, Kostas K. Kakuris, Kyrill P. Charapakhin, Andreas B. Afoninos — 2005-7-1

The aim of this study was to determine that hypokinesia (restricted motor activity) could increase potassium (K⁺) losses with decreased tissue K⁺content showing decreased K⁺ deposition. To this end, measurements were made of K⁺absorption, tissue K⁺ content, plasma K⁺ levels, fecal and urinary K⁺excretion during and after hypokinesia (HK) with and without K⁺ supplementation.

Studies conducted on male Wistar rats during a pre-hypokinetic period, a hypokinetic period and a post-hypokinetic period. Rats were equally divided into four groups: unsupplemented vivarium control rats (UVCR), unsupplemented hypokinetic rats (UHKR), supplemented vivarium control rats (SVCR) and supplemented hypokinetic rats (SHKR). SHKR and UHKR were kept in small individual cages which restricted their movements in all directions without hindering food and water consumption. SVCR and UVCR were housed in individual cages under vivarium control conditions. SVCR and SHKR consume daily 3.96 mEq potassium chloride (KCl) per day.

Absorption of K⁺, and K⁺ levels in bone, muscle, plasma, urine and feces and PA levels did not change in SVCR and UVCR compared with their pre-HK levels. During HK, plasma, fecal and urinary K⁺ levels and plasma aldosterone (PA) levels increased significantly (p<0.05) with time, while K⁺ absorption, muscle and bone K⁺ content decreased significantly (p<0.05) with time in SHKR and UHKR compared with their pre-HK values and the values in their respective vivarium controls (SVCR and UVCR). During the initial 9-days of post-HK, K⁺ absorption increased significantly (p<0.05) and plasma K⁺levels, fecal and urinary K⁺ losses and PA levels decreased significantly (p<0.05) and muscle and bone K⁺ content remained significantly (p<0.05) depressed in SHKR and UHKR compared with their pre-HK and their respective vivarium control values. During HK and post-HK periods, K⁺ absorption, bone and muscle K⁺ content, and K⁺ levels in plasma, urine and feces and PA levels were affected significantly (p<0.05) more in SHKR than in UHKR. By the 15th day of post-HK the values in SHKR and UHKR approach the control values.

The higher K⁺ losses during HK with decreased tissue K⁺ levels shows decreased K⁺ deposition. The higher K⁺loss with lower tissue K⁺levels in SHKR than in UHKR shows that K⁺ deposition decreases more with K⁺ supplementation than without. Because SHKR had shown lower tissue K⁺ content and lost higher K⁺ amounts than UHKR it was concluded that the risk of decreased K⁺ deposition and tissue K⁺ depletion is inversely related to K⁺ intake, i.e., the higher K⁺ intake, the greater the risk for decreased K⁺ deposition, and the higher K⁺ losses and the greater the risk for tissue K⁺ depletion. The dissociation between tissue K⁺ depletion and K⁺ excretion indicates decreased K⁺ deposition as the principal mechanism of tissue K⁺ depletion during prolonged HK.

Risk and Benefit of Drug Use During Pregnancy

Ferenc Bánhidy, R.Brian Lowry, Andrew E. Czeizel — 2005-7-1

Environmental teratogenic factors (e.g. alcohol) are preventable. We focus our analysis on human teratogenic drugs which are not used frequently during pregnancy. The previous human teratogenic studies had serious methodological problems, e.g. the first trimester concept is outdated because environmental teratogens cannot induce congenital abnormalities in the first month of gestation. In addition, teratogens usually cause specific congenital abnormalities or syndromes. Finally, the importance of chemical structures, administrative routes and reasons for treatment at the evaluation of medicinal products was not considered. On the other hand, in the so-called case-control epidemiological studies in general recall bias was not limited. These biases explain that the teratogenic risk of drugs is exaggerated, while the benefit of medicine use during pregnancy is underestimated. Thus, a better balance is needed between the risk and benefit of drug treatments during pregnancy. Of course, we have to do our best to reduce the risk of teratogenic drugs as much as possible, however, it is worth stressing the preventive effect of drugs for maternal diseases (e.g. diabetes mellitus and hyperthermia) related congenital abnormalities.

Primary prevention of Down's syndrome

Howard S Cuckle — 2005-7-1

Background: Antenatal screening has the capacity to detect more than 90% of Down's syndrome pregnancies leading to therapeutic abortion. Successes in recent years with such so-called 'secondary' prevention have not been matched with progress in primary prevention. Despite considerable research over many decades the principle cause of the disorder is unknown.

Methods: This paper considers three potential primary prevention strategies, (1) avoiding reproduction at advanced maternal age, (2) pre-implantation genetic diagnosis for couples who are at high risk of Down's syndrome, and (3) folic acid supplementation. The principle aetiological hypotheses are also reviewed.

Interpretation: A strategy of completing the family before a maternal age of 30 could more than halve the birth prevalence of this disorder. Women with a high a priori risk should have access to pre-implantation genetic diagnosis, which can lead to a reasonably high pregnancy rate with an extremely low risk of a Down's syndrome. The evidence suggesting an aetiological role for defective folate and methyl metabolism is not sufficient to justify an active preventative strategy of folic acid supplementation without performing a large clinical trial. Current supplementation policies designed to prevent neural tube defects may incidentally prevent Down's syndrome, provided a sufficiently high dose of folic acid is used. Further progress in primary prevention is hampered by limited aetiological knowledge and there is an urgent need to refocus research in that direction.

Birth Defects Are Preventable

Andrew E. Czeizel — 2005-7-1

An Avian Connection as a Catalyst to the 1918-1919 Influenza Pandemic

James E. Hollenbeck — 2005-5-15

The 1918 Influenza pandemic was one of the most virulent strains of influenza in history. This strain quickly dispatched previously held theories on influenza. World War One introduced new environmental stresses and speed of dissemination logistics never experienced by humans. In light of new phylogenic evidence the cause of this influenza outbreak is now being considered to have linkage to the avian influenza. Animals act as reservoirs for this influenza virus and research indicates the influenza virus often originates in the intestines of aquatic wildfowl. The virus is shed into the environment, which in turns infects domestic poultry, which in turn infects mammalian hosts. These animals, usually pigs, act as a transformer or converters; creating a strain that can more readily infect humans. Therefore swine can be infected with both avian and human influenza A viruses and serve as a source for infection for a number of species as the incidents of direct infection from birds to humans have been rare. Increased human habitation near poultry and swine raising facilities pose greater influenza outbreak risk. It was this combination of environmental factors that may have contributed to the greatest pandemic of recent times, and, moreover, similar conditions exist throughout Southeast Asia today.

Comparison of Classical and Clozapine Treatment on Schizophrenia Using Positive and Negative Syndrome Scale of Schizophrenia (PANSS) and SPECT Imaging

Mohammad Sharafi — 2005-5-10

Many neuroimaging studies of schizophrenia have shown abnormalities in the frontal cortex, limbic system, basal ganglia, temporal and parietal lobes. These findings are not specific or consistent enough to build up a coherent theory of the origin of the brain abnormality in schizophrenia. This paper describes a state-of-the-art approach of SPECT to correlate neuropsychological evaluation. PANSS scores and different brain focal abnormalities of two groups of patients receiving Clozapine and classical antipsychotic treatments were observed. A total of 20 drug-free patients, actively psychotic schizophrenic, were selected according to the DSM-IV criteria. Pre-Post-treatment was designed using PANSS and 99mTc- ECD-SPECT to assess regional Cerebral Blood Flow (rCBF). The results showed that after treatment, differences in PANSS scores were significant in both groups, with superior scores resulting from the Clozapine therapy. Results were supported by SPECT, which showed a greater improvement in the Clozapine group. Both positive and negative symptoms were improved with Clozapine as well. Before treatment, hypofrontality was the most common (85%) finding, whereas after treatment hypofrontality was mostly cleared. However, in some areas like temporal and caudate, hyperfrontality was induced. Negative symptoms showed linkage to hypofrontality in both groups before and after treatment, and both positive and negative symptoms were improved more with Clozapine therapy than with classical treatment.

Study of urban community survey in India: growing trend of high prevalence of hypertension in a developing country

Shyamal Kumar Das, Kalyan Sanyal, Arindam Basu — 2005-4-1

The prevalence pattern of hypertension in developing countries is different from that in the developed countries. In India, a very large, populous and typical developing country, community surveys have documented that between three and six decades, prevalence of hypertension has increased by about 30 times among urban dwellers and by about 10 times among the rural inhabitants. Various factors might have contributed to this rising trend and among others, consequences of urbanization such as change in life style pattern, diet and stress, increased population and shrinking employment have been implicated. In this paper, we study the prevalence of hypertension in an urban community of India using the JNC VII criteria, with the aim of identifying the risk factors and suggesting intervention strategies. A total of 1609 respondents out of 1662 individuals participated in our cross-sectional survey of validated and structured questionnaire followed by blood pressure measurement. Results showed pre-hypertensive levels of blood pressures among 35.8% of the participants in systolic group (120-139mm of Hg) and 47.7% in diastolic group (80-89 mm of Hg). Systolic hypertension (140 mm of Hg) was present in 40.9% and diastolic hypertension (90 mm of Hg) in 29.3% of the participants. Age and sex-specific prevalence of hypertension showed progressive rise of systolic and diastolic hypertension in women when compared to men. Men showed progressive rise in systolic hypertension beyond fifth decade of life. Bivariate analysis showed significant relationship of hypertension with age, sedentary occupation, body mass index (BMI), diet, ischemic heart disease, and smoking. Multivariate analysis revealed age and BMI as risk factors, and non-vegetarian diet as protective factor with respect to hypertension. Prevalence of prehypertensives was high among younger subjects - particularly students and laborers who need special attention. Role of non-vegetarian diet as a protective factor might have been related to fish-eating behavior of the sample population, who also use mustard oil as cooking medium - both of which have significant level of essential polyunsaturated fatty acids. The observed prevalence of hypertension in this study and other studies suggest the need for a comprehensive national policy to control hypertension in India, and, in other similar developing countries.

Cell Cycle Arrest by a Natural Product via G2/M Checkpoint

2005-4-1

CKBM is a natural product that exhibits a novel anti-tumor activity through the induction of cell cycle arrest and apoptosis. We have investigated its effects on cell cycle regulation using a gastric cancer cell line, AGS. The effects of CKBM on cell proliferation, cell cycle regulation and apoptosis were analyzed using BrdU (5-bromo-2'-deoxyuridine) cell proliferation assay and flow cytometric analysis, respectively. Specific cellular protein expressions were measured using Western blot analysis. Flow cytometric analysis indicated that CKBM induced G2/M cell cycle arrest and apoptosis, whereas differential protein expressions of p21, p53 and 14-3-3σ (stratifin) using Western blot analysis were enhanced. The differential expressions of p21, p53 and 14-3-3σ in AGS cancer cells after CKBM treatment may play critical roles in the G2/M cell cycle arrest that blocks cell proliferation and induces apoptosis.

A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations

2005-4-1

Background & Aims: At least 500 μg of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of folate-rich and fortified foods or folic acid from supplements on plasma total homocysteine (tHcy) concentrations, which was the aim of this study. Methods: Twenty male patients with hyperhomocysteinemia and coronary artery disease were included in a randomized, crossover intervention trial. Patients were treated daily with a combination of foods containing approximately 500 μg of folate or with one 500 μg capsule of synthetic folic acid over two five-week periods separated by a five-week wash-out period. Results: Plasma folate increased markedly (p<0.001) and plasma tHcy decreased (p<0.001) with both therapies. Folate-rich foods decreased tHcy by 8.6% (95% CI: –15.9 to –1.2) and synthetic folic acid capsules by 8% (95% CI: –13.3 to –2.7). Conclusions: This study shows, for the first time in the literature, that a folate-rich diet is as effective as folic acid capsules in decreasing plasma tHcy concentrations and adds further support to the recommendation of those diets to prevent cardiovascular disease.

Epidemiology and Prevention of Hepatitis B Virus Infection

Jinlin Hou, Zhihua Liu, Fan Gu — 2005-1-5

Hepatitis B is one of the most common infectious diseases globally. It has been estimated that there are 350 million chronic hepatitis B virus (HBV) carriers worldwide. The prevalence of chronic HBV infection varies geographically, from high (>8%), intermediate (2-7%) to low (<2%) prevalence. HBeAg-negative chronic hepatitis B (e-CHB) and occult HBV infection are two special clinical entities, and the prevalence and clinical implications remain to be explored. The predominant routes of transmission vary according to the endemicity of the HBV infection. In areas with high HBV endemicity, perinatal transmission is the main route of transmission, whereas in areas with low HBV endemicity, sexual contact amongst high-risk adults is the predominant route. HBV has been classified into 7 genotypes, i.e. A to G, based on the divergence of entire genome sequence and HBV genotypes have distinct geographical distributions. Three main strategies have been approved to be effective in preventing HBV infection. They are behavior modification, passive immunoprophylaxis, and active immunization. The implement of mass HBV immunization program is recommended by the WHO since 1991, and has dramatically decreased the prevalence of HBV infection and HCC in many countries.

Management of HBV Infection in Liver Transplantation Patients

John M. Vierling — 2005-1-5

In the absence of preventative therapy, reinfection of allografts with hepatitis B virus (HBV) after orthotopic liver transplantation (OLT) resulted in dismal allograft and patient survival. Major advances in the management of HBV-infected recipients of OLT during the past 15 years have steadily reduced the rate of reinfection, resulting in improved outcomes. Initially, long-term use of hepatitis B immune globulin (HBIG) as a source of anti-HBs antibodies was effective in preventing or delaying reinfection. Lamivudine monotherapy made it possible to suppress HBV replication prior to OLT, markedly decreasing the risk of reinfection. Although lamivudine monotherapy used before and after OLT could prevent reinfection, its effectiveness was limited by progressive development of lamivudine-resistant mutant infections. Combination therapy with HBIG and lamivudine after OLT reduced both HBV recurrence and the risk of lamivudine resistance even in patients with active HBV replication. Introduction of adefovir provided a safe, alternative oral antiviral able to treat effectively lamivudine-resistant mutants HBV. Available strategies to prevent reinfection have resulted in OLT outcomes for HBV-infected patients comparable to those for patients transplanted for non-HBV indications. In the future, combination therapies of HBIG and both nucleoside and/or nucleotide agents will undoubtedly be optimized. Development of new drugs to treat HBV will increase opportunities to combine agents to enhance safety, efficacy and prevent emergence of HBV escape mutants. New vaccines and adjuvants may make it possible to generate anti-HBs in immunosuppressed patients, eliminating the need for HBIG.

Natural History and Clinical Consequences of Hepatitis B Virus Infection

Calvin Q. Pan, Jin X. Zhang — 2005-1-5

Despite the existence of Hepatitis B vaccination, hepatitis B virus (HBV) infection is still prevalent worldwide and accounts for significant morbidity and mortality. It is encouraging that majority of patients do recover from the acute infection, however, those that progress to chronic disease state is at great risk of developing complications such as hepatocellular carcinoma, cirrhosis and liver failure. Hepatitis B virus infection can be influenced by many factors such as host immune status, age at infection, and level of viral replication. The discovery about the existence of various genotypes and its association with different geographic distribution as well as the knowledge regarding mutant species has aid us in better understanding the nature of HBV infection and in delivering better care for patients. It is especially important to recognize those individuals with HBeAg-negative chronic HBV as they have a poorer prognosis compare with their counterparts, HBeAg-positive. Tremendous progress has been made over the years in understanding the behavior and clinical course of the disease; however, the natural history of HBV is complex and we still have much to explore and learn.

High level expression of apoptosis inhibitor in hepatoma cell line expressing Hepatitis B virus

Xuanyong Lu, Matthew Lee, Trang Tran, Timothy Block — 2005-1-5

The serious result of hepatitis B (HBV) virus infection is development of hepatocellular carcinoma (HCC). However, the reason of development of HCC in HBV infected patients is still unclear. Recently, the suppression of cell apoptosis is found to relate with the development of cell carcinogenesis, therefore, the expression of apoptosis inhibitor in the virus related cancer line such as hepatoma cell line HepG2.215 was investigated. There are at least six Human apoptosis inhibitors (IAP) have been identified now. They are cIAP1, cIAP2, XIAP, NAPI, survivin and pIAP. Using gene-assay technology, we have recently compared the expression of IAPs in the HepG2.215 cells that persistently expresses Hepatitis B virus by integrated HBV genome with its parent cell line HepG2. The results suggest that there was obviously increase of cIAP2 and cIAP1 in the HepG2.215 cells versus HepG2 cells. Those observations imply a possibility of long time HBV infection could induce the over-expressing apoptosis inhibitors, furthermore, causing the liver cancer. The high expression of cIAP1 and cIAP2 in HBV expressing cells was confirmed by RT-PCR and Northern blot analysis. However, we did not find the change of NIAP and suvivin in HepG2.215 cells. In contrast, the expression of XIAP was down in the HepG2.215 cells comparing with HepG2 cells. How HBV triggers the over-expression of apoptosis inhibitor is unclear. Transient transfection of HepG2 cells with the plasmids expressing different HBV proteins such as S, M, L, X and core proteins did not give a decisive conclusion. Further study is going on now.

Advances in immunomodulating therapy of HBV infection

Chee-Kin Hui, George KK Lau — 2005-1-5

Patients with chronic hepatitis B virus (HBV) infection have a higher risk of developing liver cirrhosis and hepatocellular carcinoma. Interferon-α, lamivudine and adefovir dipivoxil are the three approved treatment for chronic HBV infection and offers the only means of preventing the development of these complications. However, the efficacy of these agents, in terms of loss of Hepatitis B e antigen with or without seroconversion to Hepatitis B e antibody, normalization of serum alanine transaminase levels, loss of serum HBV DNA, and improvement in liver histology can only be achieved in 20-30% of those treated. Long-term treatment with either lamivudine or adefovir dipivoxil can result in the development of drug resistant mutants leading to an increased length of treatment with additional nucleoside analogues. These limitations of the current antiviral therapies underline the need for alternative therapies. Specific and nonspecific immunotherapeutic strategies to restore effective virus-specific T cell responses in those with chronic HBV infection offers an interesting alternative approach. These immunotherapeutic therapies include the adoptive transfer of HBV immunity, pegylated interferon and therapeutic vaccine therapies.

A Practical Approach to Management of Chronic Hepatitis B

Ke-Qin Hu — 2005-1-5

Chronic hepatitis B (CHB) is one of the important public health problems worldwide. Major advances have been made in the treatment of CHB during the past several years. This article systemically reviews advances in the application of HBV DNA quantitation and three approved drugs for HBV treatment, and presents an updated and practical clinical approach to managing CHB. Highly sensitive PCR-based quantitation of HBV DNA makes it possible to precisely determine pre-treatment HBV load and monitor HBV DNA response during treatment. HBV DNA level, HBeAg status, degree of hepatic histological activity and fibrosis, and serum transaminases are the most important parameters in determining indication, regimen, and duration of HBV treatment. Although interferon alfa-2b, lamivudine, and adefovir are all approved as initial HBV treatment, understanding the advantages and advantages of each agent is important in choosing the best treatment for each individual patient with CHB.

Advances in Molecular Diagnosis of HBV Infection and Drug Resistance

Erwin Sablon, Fred Shapiro — 2005-1-5

Serological markers are key elements in diagnosing acute hepatitis B virus (HBV) infection and determining its possible evolution towards chronicity. Once treatment of chronic HBV is initiated with approved anti-hepadnaviral agents, such as lamivudine, interferon-alpha, or adefovir dipivoxil, the measurement of HBV DNA in serum can not only help monitor treatment efficacy but also indicates breakthrough infection should drug resistance emerge. Advances in the molecular diagnosis of drug resistance using highly sensitive methodologies such as DNA hybridization assays can further pinpoint the type of mutation responsible and, more importantly, detect upcoming viral resistance at an early stage when the variant represents only a minor fraction of the total viral population. Such new tools are especially relevant for patients at high risk for disease progression or acute exacerbation. Recent diagnostic developments including HBV genotyping and precore/core promoter assays that could well play important future roles in HBV patient management are also reviewed.

Hepatitis B Virus e Antigen Variants

Shuping Tong, Kyun-Hwan Kim, Charles Chante, Jack Wands, Jisu Li — 2005-1-5

More than 300 million people worldwide are chronically infected with hepatitis B virus (HBV). Considering the very short generation time for a virus, and the high error rate associated with the reverse transcription step of HBV replication, decades of HBV infection are probably equivalent to million years of human evolution. The most important selective force during the natural course of HBV infection appears to be the immune response. The development of anti-HBe antibody in hepatitis B patients usually correlates with reduction of HBV viremia. As a consequence, escape mutants of anti-HBe are selected. The core promoter mutants express less HBe antigen (HBeAg) through transcriptional down regulation, while precore mutants express truncated products. We recently identified additional mutations that modulate HBeAg translation initiation, proteolytic cleavage, and secondary structure maintenance through a disulfide bond. The core promoter mutants have been associated with the development of fulminant hepatitis during acute infection and liver cancer during chronic infection. Consistent with their enhanced pathogenicity, core promoter mutants were found to replicate at up to 10-fold higher levels in transfected human hepatoma cells than the wild-type virus. Moreover, some core promoter mutants are impaired in virion secretion due to missense mutations in the envelope gene. These virological properties may help explain enhanced pathogenicity of core promoter mutants in vivo.

Advances in Hepatitis B Research: From Virology to Clinical Management (A Special Issue)

Xuanyong Lu, Ke-Qin Hu — 2005-1-5