bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence‐based diagnosis
Authors: Fowler P. B. S.
Published: November 2003

Diagnosis, the most important aspect of clinical medicine, remains as much an art as a science. It depends more on skilled history taking than on examination or studying the results of tests. Evidence‐based medicine only follows when a correct diagnosis has been made. The diagnosis depends on knowing what happens rather than the more exciting academic teaching about why things happen. The factual knowledge and logic needed to make a diagnosis are discussed.
Transmission routes and clinical courses in sporadic acute hepatitis C
Authors: Sata M. , Hashimoto O. , Noguchi S. , Uchimura Y. , Akiyoshi F. , Matsukuma N. , Fukushima H. , Suzuki H. , Kage M. , Kojiro M. , Tanikawa K.
Published: November 2003

Summary. Between March 1994 and March 1996 we studied transmission routes and clinical courses in eight patients with sporadic acute hepatitis C (two men, six women). Of the eight patients, three were treated for another illness 1–2 months before the onset of hepatitis, one was a parenteral drug abuser, one had an accidental needlestick injury and two had sexual contact with a partner with chronic hepatitis C virus (HCV) infection. Clinical courses included four women whose HCV RNA and alanine aminotransferase (ALT) became persistently negative without treatment, and four men and two women with the same results following interferon (IFN) treatment. It is thought that IFN therapy may prevent the progression to chronic liver disease. Results from this study might be useful in the future management of patients with sporadic acute hepatitis C.
Effects of cirrhosis, interferon and azathioprine on adverse events in patients with chronic hepatitis C treated with ribavirin
Authors: Thevenot T. , Mathurin P. , Moussalli J. , Perrin M. , Plassart F. , Blot C. , Opolon P. , Poynard T.
Published: November 2003

Summary. To determine adverse events of ribavirin in the treatment of chronic hepatitis C, 41 patients (18 with cirrhosis), treated with ribavirin at an initial dose of 600–1200mg day‐1, were analysed retrospectively (six patients were treated twice because adverse effects during the first treatment necessitated cessation of ribavirin). Indications for ribavirin included a contraindication (n= 15) an intolerance (n= 11) or a non‐response (n= 15) to interferon (IFN). Ribavirin was combined with IFN 3 million units (MU) three times weekly for 15 patients and with azathioprine for six patients (five of whom were transplant patients). No cirrhotics and only one patient treated with ribavirin + IFN received azathioprine. The mean duration of treatment was 5 months (range 1–18 months). Sixteen of 47 treatments (34%) with ribavirin were stopped: four because of vomiting (8.5%), two for psychiatric disorder, one for dry cough, one for an unrelated cause, and eight (at 1–2 months) because of a fall in the level of haemoglobin (Hb) of 4.6 g dl‐1 (range 2.7–5.9 gdl‐1); however, according to the rules of international protocol, we would have expected only four treatments (two in patients receiving azathioprine) with Hb < 8.5 g dl‐1 to be stopped. The decrease in Hb level occurred more slowly in patients treated with IFN plus ribavirin than in patients treated with ribavirin alone and was of lower clinical significance in patients with cirrhosis than in patients without cirrhosis. After exclusion of patients receiving azathioprine, there was no significant difference in the fall of Hb level between cirrhotic and non‐cirrhotic patients and between patients treated with IFN plus ribavirin and patients treated with ribavirin alone. Interestingly, the platelet count of patients treated with IFN plus ribavirin fell less than in patients treated with IFN alone. The most important and expected adverse event associated with ribavirin was haemolysis. Anaemia < 8.5 g dl‐1, requiring cessation of ribavirin therapy, was present in 9% of patients and was worsened by azathioprine. Abdominal discomfort and dry cough were other, potentially important, clinical adverse events found in our study.
Host genetic factors influencing the outcome of hepatitis
Authors: Thursz M. R.
Published: November 2003

Summary. A strong genetic component determining the outcome of hepatitis B virus (HBV) infection has been established through twin studies. The immunopathogenesis of HBV infection is well described and it has therefore been possible to predict some gene loci, exhibiting polymorphism, may influence the outcome of HBV infection. As expected, the immune response genes in the major histocompatibility complex (MHC) on the short arm of chromosome 6 have provided confirmed susceptibility genes. In hepatitis C virus (HCV) infection the picture is not so clear although comparison of the known immunological phenomena with those of HBV suggest that polymorphisms in the MHC may also influence disease outcome. Identification of susceptibility genes, which modify disease phenotype, may assist in predicting natural outcome of infection or response to therapy.
In situ investigation of Fas/FasL expression in chronic hepatitis B infection and related liver diseases
Authors: Luo K.‐X. , Zhu Y.‐F. , Zhang L.‐X. , He H.‐T. , Wang X.‐S. , Zhang L.
Published: November 2003

Summary. To evaluate Fas/FasL expression in hepatitis B virus‐related chronic liver disease, liver biopsies from 44 such cases were studied immunohistochemically. FasL was detected in the infiltrating lymphocytes and both FasL and Fas were found in the hepatocytes. The Fas and FasL‐positive cells were mostly found at the advancing edges of interphase hepatitis, and Fas/FasL expression was closely correlated with the inflammatory activity. Unexpectedly, FasL was also expressed in liver cirrhotic nodules, particularly in those with hepatocellular carcinoma with or without inflammation. These results suggest that the factors which induce hepatocyte transformation might also trigger FasL expression and promote FasL/Fas‐mediated apoptosis.
Importance of age in chronic hepatitis C virus infection
Authors: Wong V. , Caronia S. , Wight D. , Palmer C. R. , Petrik J. , Britton P. , Alexander G. J. M.
Published: November 2003

Summary. This study was designed to investigate the value of liver biopsy in the management of patients with chronic hepatitis C virus infection and to identify risk factors for fibrosis. It was a prospective audit of clinical, biochemical, virological and radiological features for predicting liver fibrosis in 140 consecutive patients seropositive for antibody against hepatitis C virus. Seventy‐five per cent of patients were asymptomatic and 69% had no clinical signs of chronic liver disease. Serum transaminase levels were normal in 44% of patients, less than twice normal in 35% and more than twice normal in 21%. Ultrasound scan was unremarkable in 85%. Sixty‐nine per cent of patients were viraemic at the time of liver biopsy. Liver histology revealed that fibrosis was absent in only 10% of patients (stage 0) while cirrhosis was evident in 7% (stage 5). Liver fibrosis was detected in 90% of patients (stage 1, 11%; stage 2, 41%; stage 3, 21%; and stage 4, 10%). Univariate analysis showed that increasing age, clinical signs of chronic liver disease and abnormal ultrasound scan findings were associated with liver fibrosis (P < 0.05); however, multiple linear regression analysis of all the clinical features did not reveal a useful model (sensitivity 42% and specificity 23%) for predicting liver fibrosis. Hence, no combination of clinical, biochemical, virological or radiological data was reliable in discriminating the stage of liver fibrosis in patients with chronic hepatitis C virus infection. However, older patients, especially those with clinical signs of chronic liver disease and abnormal ultrasound scan findings, were more likely to have advanced fibrosis. We recommend liver biopsy as the single most important investigation in detecting liver fibrosis.
Functional implications of hepatitis B surface antigen (HBsAg) in the T cells of chronic HBV carriers
Authors: Nagaraju K. , Naik S. R. , Naik S.
Published: November 2003

Summary. This study was undertaken to investigate the role of T‐lymphocyte‐derived soluble factors in the maintenance of the hepatitis B virus (HBV) chronic carrier state. Cell‐free supernatants from the peripheral blood T lymphocytes of chronic HBV carriers were produced by incubating them for 48h in tissue culture medium. These supernatants were added to in vitro hepatitis B s antibody (HBsAb)‐producing cultures of peripheral blood mononuclear cells from hepatitis B surface antigen (HBsAg) vaccinees stimulated with HBsAg or pokeweed mitogen. T‐cell supernatants from chronic carriers suppressed in vitro HBsAb antibody synthesis, whereas those from control subjects did not. This suppression was antigen specific as the supernatants did not suppress synthesis of total IgG or IgM. HBV viral sequences were demonstrable, by Southern and dot‐blot hybridization, in the T cells secreting this factor. We also demonstrated the presence of HBsAg in T‐cell supernatants derived from these cells. These results show that HBsAg of T‐cell origin may have a role in suppressing HBsAb production. Our observations point to the role of HBsAg‐specific cellular and humoral responses in favouring persistence of the chronic HBV carrier state.
Hepatitis C virus genotypes in Australia
Authors: McCaw R. , Moaven L. , Locarnini S. A. , Bowden D. S.
Published: November 2003

Summary. The relative distribution of Australian hepatitis C virus (HCV) genotypes was determined for 500 isolates. Genotyping was performed using a commercial reverse phase hybridization assay after amplification of the 5′ untranslated region of HCV by the polymerase chain reaction. Australian isolates comprised, predominantly, genotype 1 (55%) and genotype 3 (38%) with genotype 2 accounting for only 7%. Genotype 3a was the most common subtype. When the major risk groups of injecting drug users or transfusion‐acquired hepatitis C were compared, there was a significantly higher incidence of genotype 1b in the transfusion‐acquired group (P < 0.03). When the age of the patients was analysed, genotype 3a was more prevalent in the 21–40‐year age group than the 41–60‐year age group (P < 0.05). There was no significant difference in genotype distribution between males and females. HCV genotypes 1, 2 and 3 are most often found in developed countries but the relatively high prevalence of genotype 3a in Australia is unusual.
Virological, biochemical and histological effects of human lymphoblastoid interferon in Swedish patients with chronic hepatitis C
Authors: Garson J. A. , Uhnoo I. , Whitby K. , Braconier J. H. , Deaville R. , Duberg A. , Wallmark E. , Wiström J. , Goldin R. D. , Spacey B.
Published: November 2003

Summary. Thirty‐eight Swedish patients with chronic hepatitis C were randomly assigned to receive either 3 million units (MU) or 5 MU of human lymphoblastoid interferon‐α‐n1 (Wellferon) three times per week for either 6 or 12 months. The patients were monitored biochemically, histologically and by quantitative polymerase chain reaction for circulating HCV RNA, during therapy and for the following year. Overall, 22 (58%) of the patients lost detectable hepatitis C virus (HCV) viraemia during therapy but eight of these patients relapsed during follow‐up, leaving 14 (37%) sustained responders. Patients infected with HCV non‐type 1 genotypes were significantly more likely to achieve a sustained response than were those infected with HCV type 1 (63% vs 10.5%, P= 0.001). Sustained virological responses were also associated with lower pretreatment viraemia level, younger age, absence of cirrhosis and the higher interferon dosage regimens but these associations failed to reach statistical significance. In 97% of patients there was concordance between virological and biochemical responses, and a statistically significant (P= 0.005) improvement in the Knodell histological activity index was observed in the virological sustained responders.
Epidemiological study of viral hepatitis types A, B, C, D and E among Inuits in West Greenland
Authors: Langer B. C. A. , Frösner G. G. , von Brunn A.
Published: November 2003

Summary. A descriptive study was performed to evaluate the relative frequencies and molecular epidemiological features of viral hepatitis types A to E among the Inuit population in West Greenland. Serum samples were collected from 503 Inuits (186 males and 317 females; mean age 35 years; range 7–79 years) and were tested for markers of viral hepatitis infection. The hepatitis A prevalence averaged 54%, with a significant rise from 9% to 50% between the second and third decade of life. As for hepatitis B, 42% of the total study population showed serological evidence of current or past hepatitis B virus (HBV) infection and 7% were hepatitis B surface antigen (HBsAg) carriers. Among the carriers, 6% were also positive for hepatitis B e antigen (HBeAg), and HBV DNA could be detected in 49% of carriers by polymerase chain reaction. Typing of the HBV isolates revealed genomic group D in 83% (serotype ayw 2) and group A in 17% (serotype adw 2). Less than 1% of the study population had antibodies to the hepatitis C virus. None were positive for HCV RNA. Serological evidence of hepatitis D infection was found in 7% of those with hepatitis B helper virus infection markers and in 40% of the HBsAg carriers. As for hepatitis E, 3% of the Inuits showed reactivity in an enzyme immunoassay that detected hepatitis E virus antibody. HEV RNA could not be detected.
Sequence variation and phylogenetic analysis of the 5‘ terminus of hepatitis G virus
Authors: Linnen J. M. , Fung K. , Fry K. E. , Mizokami M. , Ohba K. , Wages J. M. , Zhang‐Keck Z.‐Y. , Song K. , Kim J. P.
Published: November 2003

Summary. We determined the nucleotide and deduced amino acid sequence of the 5′ terminus of the hepatitis G virus (HGV) genome from isolates of varied geographical origins. Our analysis showed that the putative 5′ non‐coding region (NCR) contains several blocks of highly conserved sequences that may be useful for the development of a reverse transcriptase—polymerase chain reaction (RT‐PCR) assay for detection of HGV RNA. Overall, the degree of conservation within the 669‐nucleotide (nt) 5′ terminal sequence was found to range from 99.5% to 86% sequence identity. We also showed that the HGV NCR from some isolates contained conserved insertions or deletions that altered the translational reading frames at the 5′‐end of the genome, resulting in different sizes of predicted polyproteins encoded by genomes of individual isolates. Specifically, the insertions/deletions affected the size of the peptide preceding the putative first envelope (E1) protein. Phylogenetic analysis of the nucleotide sequences suggested that the isolates examined can be classified into distinct groups that may be useful for studying the molecular evolution of HGV and possible relationships between isolate sequence characteristics and infection patterns.
The molecular basis of hepatitis B e antigen (HBeAg)‐negative infections
Authors: Miyakawa Y. , Okamoto H. , Mayumi M.
Published: November 2003

Hepatitis B e antigen (HBeAg)‐negative infections are an unusual form of chronic hepatitis B virus (HBV) infection in which viral replication and liver damage persist despite antibodies against HBeAg. This form of HBV may be associated with fulminant hepatitis. The molecular basis for an HBeAg‐minus phenotype has been extensively studied and is most often a result of mutations in the precore region. However, other mutations can give rise to this phenotype and their investigation and characterization may reveal new insights into the pathogenesis of chronic viral hepatitis.
The spectrum of extrahepatic manifestations in hepatitis C virus infection
Authors: Hadziyannis S. J.
Published: November 2003

Infection with the hepatitis C virus affects not only the liver but also non‐hepatic tissues and may combine with many unrelated diseases and morbid conditions. A number of extrahepatic manifestations have already been recognized. For some of the extrahepatic disorders their association with HCV infection is well established while for others it remains probable or weak. Here, emphasis is given to the well‐established extrahepatic manifestations of mixed cryoglobulinaemia, thyroid abnormalities and lichen planus as well as to the newly recognized association with diabetes mellitus, thrombocytopenia and the antiphospholipid syndrome. Pathogenetic mechanisms of extrahepatic and autoimmune features in HCV infection are still unclear and therapeutic decisions in such conditions are difficult. Data on the efficacy and side‐effects of therapy with interferon‐α and corticosteroids are reviewed and some practical guidelines for treatment are given.
Risk factors for acute hepatitis B: a case‐control study
Authors: Sagliocca L. , Stroffolini T. , Amoroso P. , Manzillo G. , Ferrigno L. , Converti F. , Palumbo F. , Izzo E. , Mele A.
Published: November 2003

Over the period 1989–1991 a case‐control study was carried out in the area of Naples comparing 162 subjects with acute hepatitis B and 788 hospitalized control subjects. The results of multivariate analysis showed that surgical intervention (odds ratio 3.8; 95% CI 1.2–11.7), household contact with an hepatitis B surface antigen (HBsAg) positive carrier (odds ratio 2.7; 95% CI 1.1–6.7) and intravenous drug use (odds ratio 13.0; 95% CI 3.2–52.7) were risk factors independently associated with hepatitis B. No association was found with the other risk factors considered, such as blood transfusion, hospitalization, other percutaneous exposures, dental therapy, contact with an icteric case, barber shop shaving and two or more sexual partners. As a significant proportion of the general population undergoes surgical intervention, efficient procedures for sterilization of instruments should be implemented, together with the use of disposable materials, to control the spread of HBV infection in surgical settings.
The clinical significance of the detection of hepatitis GBV‐C RNA in the serum of patients with fulminant, presumed viral, hepatitis
Authors: Haydon G. H. , Jarvis L. M. , Simpson K. J. , Hayes P. C. , Simmonds P.
Published: November 2003

In a significant number of cases of fulminant (presumed viral) hepatitis worldwide, no aetiological agent has been identified. Recently, it has been suggested that a newly described flavivirus, GBV‐C, is responsible for some of these cases. This study aimed to assess the clinical significance of GBV‐C RNA, demonstrated by reverse transcriptase–polymerase chain reaction (RT–PCR), in the serum of patients with fulminant non‐A to E hepatitis. Twenty‐three consecutive cases of non‐A to E fulminant hepatitis were included in the study. GBV‐C RNA was reverse transcribed and amplified using two RT–PCR based detection methods. Medical records were examined to assess clinical history, duration and mode of infection, transfusion history, liver histology and clinical outcome. Five (three female, two male; mean age 21.2 years) of 23 patients had GBV‐C RNA detected in their serum by RT–PCR; all five patients were RT–PCR positive following amplification by primers specific for the 5' non‐coding region (NCR), whilst four were positive by primers for the NS3 region. Prior to the onset of illness, two patients had risk factors for transmission of an infectious agent; however, all five patients had been transfused during their illness, prior to testing for GBV‐C. Of these, two (of two in whom serum was available) were negative for GBV‐C after the onset of fulminant hepatitis but before their first transfusion. This study does not support the hypothesis that the detection of hepatitis G virus (HGV)/GBV‐C RNA in the serum of patients with fulminant hepatitis indicates a causal association. However, it does demonstrate that a careful transfusion history and screening of blood products is vital before the importance of GBV‐C in the aetiology of fulminant hepatitis can be established.
Organ and species specificity of hepatitis B virus (HBV) infection: a review of literature with a special reference to preferential attachment of HBV to human hepatocytes
Authors: De Meyer S. , Gong Z. J. , Suwandhi W. , van Pelt J. , Soumillion A. , Yap S. H.
Published: November 2003

Summary. Hepatitis B virus (HBV) infection is still a major public health problem worldwide. Although much information about the molecular biology of HBV has been gained in the last decades, little is known about the mechanism of attachment and penetration of the HBV particle into human hepatocytes. The HBV envelope proteins are important for the interaction between the HBV particle and the hepatocyte plasma membrane. Although initially it was suggested that the preS2 domain could act, via polymerized human serum albumin, as an attachment site to human hepatocytes, in recent years other observations showed that the preS1 domain is probably the most important attachment site to human hepatocytes. However, controversial findings on cellular proteins for binding to the preS1 domain has been described, namely the IgA‐, the IL6‐, the asialoglycoprotein receptor and GAPD. Although the preS1 attachment site may be important, apo H has been shown to bind specifically to small HBsAg. Recently, we have identified human liver Annexin V as a specific small HBsAg‐binding protein. In a preliminary report, the direct involvement of human Annexin V in the initial step of HBV infection has been desmonstrated. A rat hepatoma cell line, which does not express human Annexin V and which is not infectable by HBV, gained the ability to become infected by HBV after transfection with human Annexin V. This result may facilitate the progress of HBV receptor research and elucidate the molecular mechanism of the initial step of HBV infection.
A model to predict long‐term sustained response to interferon therapy in chronic hepatitis C
Authors: Noventa F. , De Salvo G. L. , Chemello L. , Pontisso P. , Alberti A.
Published: November 2003

Interferon therapy is used widely for chronic hepatitis C but only a minority of treated patients achieve a long‐lasting sustained response. We have developed, by logistic regression, a mathematical model to estimate the probability of sustained response in an individual patient with chronic hepatitis C when treated with interferon‐α (IFN‐α). The model, which includes age, sex, disease duration, pretreatment serum γ‐glutamyl‐transpeptidase, alanine aminotransferase and virus genotype, was developed from a database of 307 patients and validated in a new set of 200 patients. It performed well as goodness‐of‐fit (P= 0.71 and P= 0.15 in the development and test sample, respectively) and discrimination (area under receiver operating curve = 0.79 in the development and 0.78 in the test sample, respectively). This model may provide decision support in the treatment of chronic hepatitis C with IFN‐α.
High prevalence of hantavirus infection in a group of Chinese patients with acute hepatitis of unknown aetiology
Authors: Meng G. , Lan Y. , Nakagawa M. , Maehara T. , Mitani K. , Tomiyama T. , Che X. G. , Ohkubo A.
Published: November 2003

Summary. In southwestern China, small but substantial numbers of patients with acute hepatitis were found without known hepatropic viral infections (hepatitis A, B, C, D or E, cytomegalovirus, Epstein‐Barr virus) and were receiving no hepatotoxic drugs. Prevalence of antibodies, both neutralizing and specific immunoglobulin (Ig)M and IgG, to Hantaan virus were evaluated in a cohort of 136 such patients: 83 were of unknown aetiology, 53 had known viral hepatitis and 59 healthy subjects acted as controls. The results showed that the incidence of neutralizing antibody to Hantaan virus in acute hepatitis patients with non‐hepatitis A‐E virus infections (13 of 83) was significantly higher than in those with A‐E infections (0 of 53, P<0.01). Furthermore, the incidence of specific IgM antibody to Hantaan virus in acute hepatitis patients with non‐hepatitis A‐E virus infections (6 of 83) was significantly higher than in those with A‐E infections (0 of 53, P<0.05) and in healthy subjects (0 of 59, P<0.05). These findings suggest that Hantaan virus may be an important agent, contributing, at least in southwestern China, to a significant number of the cases of acute hepatitis of unknown aetiology. This hantavirus infection resulted in an acute hepatitis, differing from the typical diseases: haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS).
Age and platelet count: a simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus
Authors: Poynard T. , Bedossa P.
Published: November 2003

The aim of this study was to identify clinical and biological factors associated with histological lesions in patients with chronic hepatitis C and to construct a simple diagnostic index. A database consisting of 500 patients with untreated biopsy‐proven chronic non‐A non‐B hepatitis was used. Liver biopsies were reviewed, blind, by a panel of pathologists. Patients were classified according to the presence of necroinflammatory lesions (histological activity) and fibrosis. The diagnostic value of nine clinical and 10 biological factors was assessed using logistic regression analysis, sensitivity, specificity and predictive values, and a score was constructed combining the most significant factors identified. The validation used an independent population of 120 patients. Serum platelet concentration and age were the two main factors significantly and independently correlated with the presence of fibrosis and/or histological activity. A simple score referred to as AP, combining age and platelet count, varied from 0–10. For the presence of significant histological disease (moderate to severe necroinflammatory lesions and/or septal fibrosis to cirrhosis), an AP score of 6 or more had a specificity of 0.93 and a sensitivity of 0.52%. In the validation population, the area under the curve was 0.690 ± 0.085, not significantly different from that of the first population, 0.763 ± 0.043. Hence, a simple score combining age and platelet count enabled the accurate prediction of the presence of activity and fibrosis in patients infected with the hepatitis C virus. When this score reached 6, liver biopsy could be avoided owing to its high predictive value. However, the negative predictive value was not high enough to prevent a liver biopsy in patients with a lower score.
Inhibition of hepatitis B virus by retroviral vectors expressing antisense RNA
Authors: Ji W. , Si C. W.
Published: November 2003

Summary. Two retroviral vectors carrying an antisense gene from the hepatitis B virus (HBV) preS/S or preC/C were constructed and used to infect the human hepatoblastoma cell line 2.2.15, which expresses HBV surface antigen (HBsAg), HBV e antigen (HBeAg) and releases HBV particles. The results showed that the inhibitory effects of antisense gene transfer, mediated by retroviral vectors on the expression of HBV antigens, appeared as early as day 3 after transduction, reached a maximum on day 5 and persisted for at least 11 days. Our data indicate that, on day 5 after introduction, antisense preS/S inhibited HBsAg and HBeAg expression by 71% and 23%, and the antisense preC/C inhibited HBsAg and HBeAg expression by 23% and 59%. HBV DNA production, in the supernatant of the 2.2.15 cells transduced with either antisense preS/S or preC/C, was also reduced on day 5, but the viability of the 2.2.15 cells was not affected. Our results demonstrate that the replication and expression of HBV can be inhibited through antisense gene transfer mediated by retroviral vectors and that the antisense‐preC/C or antisense‐preS/S may be potentially useful for clinical gene therapy against HBV.
Epidemiology of hepatitis E virus infection
Authors: Balayan M. S.
Published: November 2003

Summary. Hepatitis E is an acute, icteric, self‐limiting disease, which is spread widely in many tropical and subtropical countries where it occurs both in the form of epidemics of variable magnitude or sporadically. Hepatitis E affects young adults, rather than children, and causes a high mortality rate, particularly in pregnant women. In industrialized countries this disease occurs occasionally as imported sporadic cases. The aetiological cause of hepatitis E is a virus, hepatitis E virus (HEV), which is temporally classified as a member of the Calicivirus family, although its genomic composition is unique. There are experimental data as well as epidemiological observations allowing us to assume that hepatitis E may be a zoonosis as HEV is pathogenic for some domestic and wild animals. Recently, serological assays based on the use of recombinant or synthetic antigens were developed and applied to determine the prevalence of antibody to HEV (anti‐HEV) in various epidemic and non‐epidemic settings. In suspected hepatitis E cases, anti‐HEV seropositivity was detected at an elevated rate but the overall seroprevalence of anti‐HEV in normal human populations of endemic areas appeared to be unexpectedly low. A low but constant presence of anti‐HEV seropositivity was observed also in non‐endemic industrialized countries. In some of these countries, anti‐HEV seropositivity was accumulated in groups of patients with various liver and non‐liver pathologies and certain groups at risk for blood‐borne infections.
Tumour necrosis and microvascular proliferation are associated with 9p deletion and CDKN2A alterations in 1p/19q‐deleted oligodendrogliomas
Authors: Godfraind C. , Rousseau E. , Ruchoux M.‐M. , Scaravilli F. , Vikkula M.
Published: November 2003

A subset of oligodendrogliomas and oligoastrocytomas has been associated with 1p/19q deletion. Subsequently, this genetic alteration was linked to chemosensitivity and classic histology of oligodendrogliomas. Tumoural progression includes deletions of 9p, 10q and alterations of CDKN2A. However, these (epi)genetic changes have not been associated with specific histological features. In a series of 45 gliomas including oligodendrogliomas, oligoastrocytomas and astrocytomas, deletions of chromosomal regions implied in these tumours (1p, 9p, 10, 17p13, 19q and 22) were looked for by microsatellite analysis. Tumours that were deleted for 1p and 19q were selected. Subsequently, presence of deletions in the other studied regions, (epi)genetic changes in p14ARF, CDKN2A and CDKN2B, as well as histological features, were associated to these tumours. 1p/19q deletion was observed in 22 tumours. Twenty‐one of them presented regions of classic histology of oligodendroglioma. A deletion of 9p was found in eight of them, always in association with tumour necrosis and/or microvascular proliferation. In addition, (epi)genetic alterations of CDKN2A were observed in 71% of these tumours. Presence of regions of classic histology of oligodendroglioma in a tumour sample is predictive of 1p/19q deletions. Necrosis and/or microvascular proliferation are signs of an additional 9p deletion. Finally, as CDKN2A (epi)genetic alterations were found in 71% of the 1p/19q/9p‐deleted oligodendrogliomas, CDKN2A may have a role in oligodendroglioma‐associated microvascular proliferation.
Caspase‐dependent and caspase‐independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat
Authors: Ferrer I. , Friguls B. , Dalfó E. , Justicia C. , Planas A. M.
Published: November 2003

Transient focal ischaemia by middle cerebral artery occlusion (MCAO) may produce cell death, but the mechanisms leading to cell death differ in the infarct core and in the penumbra, the immediate zone surrounding the infarct core. In the present study, transient focal ischaemia to adult rats was produced by intraluminal occlusion of the middle cerebral artery for 1 h followed by 0 h (n = 6), 1 h (n = 10), 4 h (n = 8), 6 h (n = 2) and 12 h (n = 3) of reperfusion. The present model of ischaemia causes a large cortico‐striatal infarct extending through the mediolateral cortex and dorsolateral striatum at 12 h. The expression and subcellular distribution of several proteins involved in apoptosis have been examined in the penumbra and in the infarct core by using combined methods of immunohistochemistry, cell subfractionation and Western blotting. Transient focal ischaemia by MCAO results in activation of complex signal pathways for cell death in the penumbra. Increased expression of Bcl‐2 and Bax, but not of Bcl‐x, occurs in the penumbra at the time when Bax translocates from the cytosol to the mitochondria, cytochrome c is released to the cytoplasm and active caspase‐3 is expressed. Bax translocation, cytochrome c release and active caspase‐3 are observed at 4 h, but not at 1 h, following reperfusion, and together indicate activation of the caspase‐dependent pathway of apoptosis in the penumbra. In contrast, reduced Bax expression but not Bax translocation and cytochrome c release occurs in the infarct core, thus suggesting apoptosis signals restricted to the penumbra. In addition, increased expression of an apoptosis‐inducing factor in the cytoplasm and nuclei of selected cells shows, for the first time, activation of the caspase‐independent mitochondrial pathway in the penumbra following transient focal ischaemia and reperfusion.
Astrocyte characterization in the multiple sclerosis glial scar
Authors: Holley J. E. , Gveric D. , Newcombe J. , Cuzner M. L. , Gutowski N. J.
Published: November 2003

Dense astrocytic scarring in chronic multiple sclerosis (MS) plaques produces an inhibitory environment which can impede tissue repair. Animal studies have shown that the antigenic phenotype of the most abundant cell type in the brain, the astrocyte, varies depending on astrocyte type and location. To identify the phenotype of scar astrocytes (SAs) in chronic lesions, markers of reactive astrocytes characterized in animal studies were investigated. To date these are the only established markers. Cerebral subventricular deep white matter from normal control, MS normal appearing white matter and lesions (acute, subacute and chronic) were examined by immunohistochemistry and immunoblotting. The antigenic profile of SAs revealed significant modification of astrocyte protein expression in chronic MS lesions. SAs express nestin, embryonic neural cell adhesion molecule, fibroblast growth factor receptor 4, epidermal growth factor receptor, nerve growth factor and a subpopulation of SAs also express basic fibroblast growth factor. These are in addition to the expected markers glial fibrillary acidic protein, vimentin, and the tenascins C and R. Therefore, an SA antigenic phenotype has now been defined. This knowledge may allow the development of therapeutic strategies that prevent scar formation and promote tissue repair.
Anatomically based guidelines for systematic investigation of the central somatosensory system and their application to a spinocerebellar ataxia type 2 (SCA2) patient
Authors: Rüb U. , Schultz C. , Del Tredici K. , Gierga K. , Reifenberger G. , De Vos R. A. I , Seifried C. , Braak H. , Auburger G.
Published: November 2003

Dysfunctions of the somatosensory system are among the clinical signs that characterize a variety of polyglutamine or CAG‐repeat diseases. Deficits within this system may hinder the perception of potential threats, be detrimental to somatomotor functions, and result in uncoordinated movements, ataxia, and falls. Despite the considerable clinical relevance of such deficits, however, no systematic pathoanatomical studies of the central somatosensory system in polyglutamine diseases are currently available. The present paper has two goals: (1) re‐commendation of an economical tissue sampling method and optimized histological processing of this tissue to allow rapid and reliable evaluation of the structural integrity of all known relay stations and interconnecting fibre tracts within this complex system, and (2) the proposal of guidelines for a rapid and detailed pathoanatomical investigative procedure of the human central somatosensory system. In so doing, we draw on the current state of neuroanatomic research and apply the methods and guidelines proposed here to a 25‐year‐old female patient with spinocerebellar ataxia type 2 (SCA2). The use of 100 µm serial sections through the SCA2 patient's central somatosensory components showed that obvious neuronal loss occurred in nearly all of the relay stations of this system (Clarke's column; cuneate, external cuneate and gracile nuclei; spinal, principal and mesencephalic trigeminal nuclei; ventral posterior lateral and ventral posterior medial nuclei of the thalamus), whereas the majority of interconnecting fibre tracts (dorsal spinocerebellar tract; cuneate and gracile fascicles; medial lemniscus; spinal trigeminal tract, trigeminal nerve and mesencephalic trigeminal tract) displayed signs of atrophy accompanied by demyelinization. These pathological findings suffice to explain the patient's impaired senses of vibration, position and temperature. Moreover, together with the lesions seen in the motor cerebellothalamocortical feedback loop (pontine nuclei, deep cerebellar nuclei and cerebellar cortex, ventral lateral nucleus of the thalamus), they also account for the somatomotor deficits that were observed in the young woman (gait, stance, and limb ataxia, falls, and impaired writing). In proposing these new guidelines, we hope to enable others to study the hitherto unknown morphological counterparts of somatosensory dysfunctions in additional CAG‐repeat disease patients.
Sudden infant death syndrome and parental smoking — a literature review
Authors: Golding Jean
Published: November 2003

There are a variety of methodological problems with published studies of parental smoking and sudden infant death syndrome (SIDS), with over‐control the most consistent and problematic. Nevertheless, even though this is likely to minimise the true magnitude of relationships, the results are consistent. There are five cohort studies with prospectively collected information on maternal smoking in pregnancy: all show strong and statistically significant relationships that were dose dependent–the more cigarettes the mother had smoked, the more at risk was the baby of SIDS. Similar results have been shown from the case–control studies in which information has been collected retrospectively from parents or birth certificates. There are data from several studies indicating that environmental tobacco smoke (ETS) is also important. Since it has not yet been possible to determine conclusively whether associations are with smoking (or ETS) during pregnancy or postnatally, it is concluded that both should be discouraged.
The relationship between maternal birthweight and gestational age in twins and singletons and those of their offspring in Norway
Authors: Glinianaia Svetlana , Magnus Per , Skjæven Rolv , Bakketeig Leiv
Published: November 2003

In order to elucidate whether maternal plurality affects offspring intrauterine growth, the relationship between birthweight and gestational age of twins and singletons and those of their first singleton liveborn children in Norway was studied using data from the Medical Birth Registry. The population‐based sample consisted of 49 698 mother–offspring pairs (48 842 with singleton and 856 with twin‐mothers). In bivariate analyses, no significant differences in mean birthweight and gestational age of offspring of twin and singleton mothers were found, although the mean birthweight and gestational age of the twin‐mothers themselves were significantly lower than those of singletons (819 g and 14 days respectively). In multiple regression analysis, the expected birthweight of offspring was 230.3 g (95% CI: 193.2–267.4 g) higher when the mother was a twin than when the mother was a singleton, when controlling for non‐standardised maternal birthweight. When adjusting for relative maternal birthweight (z‐score), the association between maternal plurality and offspring birthweight was not statistically significant. The results suggest that being born as a twin has no substantial consequences on offspring growth in utero and show that mean differences in birthweight between twins and singletons should be standardised when both groups are included in multivariate studies.
Evaluation of prenatal care information on birth certificates
Authors: McDermott Jeanne , Drews Carolyn , Green Diane , Berg Cynthia
Published: November 2003

Misclassification frequently leads to bias in epidemiological studies, and causes concern for perinatal epidemiologists interested in using birth certificates as a data source. We used a maximum likelihood method to estimate the classification probabilities (conditional probabilities that indicate the probability of classification in a particular category, given the person's true category) of two data sources for a three‐category outcome of prenatal care. The probability that women receiving adequate or inadequate care were correctly classified was estimated to be greater than 90%. The probability was much lower (< 35%) that women receiving intermediate care were correctly classified. The misclassification of women from the intermediate category resulted in poor predictive values (< 70%) of women classified as receiving either adequate or inadequate care. Because of these findings, we combined the adequate and intermediate categories to form a two‐category classification system. This revision resulted in higher positive predictive values (> 90%) with only a slightly lower classification probability (> 85%) for the combined category. We conclude that the degree of accuracy for a two‐category classification of prenatal care based upon birth certificate information is acceptable, but we question the accuracy of indices of prenatal care with more than two categories.
Clinical approach to the analysis of causes of death in the first two years of life of very‐low‐birthweight infants in a multicentre setting
Authors: Corchia Carlo , Spagnolo Amedeo , de Vonderweid Umberto , Zorzi Carlo , Chiandotto Valeria , Chiappe Stefano , Colarizi Patrizia , Didato M. , Paludetto Roberto
Published: November 2003

Mortality in the first 2 years of 634 very‐low‐birthweight infants admitted to eight neonatal intensive care units in Italy, and the factors associated with the net probability of death from each cause, were studied by means of the Cox proportional hazard model. A clinical classification of the causes of death was used. Overall mortality was 33.7% (intercentre range 12.6–52.9%). The highest cause‐specific mortality rates were observed for respiratory problems, intra‐ventricular haemorrhage (IVH) and infections (14.5%, 6.3% and 5.7% respectively). The leading causes of death were respiratory problems and IVH in the first week of life, infections from the second week up to the end of the first month, and bronchopulmonary dysplasia (BPD) afterwards. Birthweight <1000 g, gestational age <30 weeks, absence of spontaneous respiratory activity, unknown body temperature and pH <7.20 at admission were associated with death from respiratory problems and IVH. Male sex, birthweight <1000 g and unknown body temperature at admission were associated with death from BPD. Mortality from infections was higher in one centre; no other differences emerged among the eight NICUs. The classification of the causes of death employed and the use of the net probabilities of death appear as practical and useful instruments to study the relationship between specific aspects of medical care and mortality, and to investigate the reasons for differences in performance between neonatal units.
Childhood influences on adult health: a review of recent work from the British 1946 national birth cohort study, the MRC National Survey of Health and Development
Authors: Wadsworth M.E.J. , Kuh D.J.L.
Published: November 2003

Research in this study has shown that growth in utero and early‐life development were associated with a range of adult outcomes, including blood pressure, respiratory function and schizophrenia. It has also been shown that childhood social and educational factors are strongly associated with adult mental and physical health, and with adult health‐related behaviour. It is suggested that the observed long‐term effects of early‐life physical development do not represent an inevitable outcome of childhood development, but one which is mediated by the chain of social factors that also begins in early life. The conclusions emphasise that since the social and economic circumstances that affect child health have changed greatly in recent years in some ways which are particularly adverse, we need now to be aware of the implications of such change not only for the health of children today, but also for their health in adulthood.
Rubidium transport in the cyanobacterium Synechococcus R‐2 (Anacystis nidulans, S. leopoliensis) PCC 7942
Authors: RITCHIE R. J.
Published: November 2003

Synechococcus R‐2 is a unicellular blue‐green alga. The cells will grow on Rb+ as a substitute for K+ but at a slower rate (t2∼ 15 h versus 12 h). Potassium is not, strictly speaking, an essential element for Synechococcus. Rubidium duxes (using 86Rb+) are much slower than those of potassium, about 1 nmol m−2 s−1 in the light (0.35 mol m−3 Rb+). 86Rb+ fluxes in the dark are about 0.1 nmol m−2 s−1. These fluxes are very slow compared to those of Na+ and other ions. Isotopic influx of Rb+ can supply sufficient Rb+ to keep up with the demands for growth, but the net dux needed to keep up with growth in the light is a large proportion of the total observed dux. Kinetic studies of Rb+ uptake versus [Rb+] show two uptake phases consistent with a high‐affinity and a low‐affinity system. Both systems appear to be light‐activated. Transport of Rb+ appears to be passive at pHo 10 in the light and dark. There is no case for active transport of Rb+ at pHo 7.5 in the light, but a marginal case for active uptake in the dark (about 3 kJ mol−1). There is only a small effect of Na+ upon Rb+ transport. 86Rb+ should not be used in place of 42K+ in K+ nutrition studies as the details of Rb+ transport are different to those of K+ transport.
Function of leaf hamamelitol as a compatible solute during water stress treatment of Hedera helix L.
Authors: MOORE B. d. , TALBOT J. N. , SEEMANN J. R.
Published: November 2003

Hamamelitol is an unusual branched‐chain sugar alcohol previously suggested to function as a leaf compatible solute. In this study, we have examined the leaf metabolism and intracelluiar compartmentalization of hamamelitol and other soluble sugars during long‐term water stress treatment of Hedera helix (English ivy). Total leaf hamamelitol content was relatively low in greenhouse control plants, but increased 2‐fold during water stress treatment to levels approaching those observed in field‐grown plants (6–7 μmol g−1 fresh weight). Using density gradient fractionation with non‐aqueous solvents, we showed that hamamelitol occurs primarily in the cytoplasm and vacuoles of leaf mesophyll cells. During water stress treatment most of the increase in leaf hamamelitol occurred in the mesophyll cytoplasm, compensating osmotically for a decrease in cytoplasmic sucrose concentration. The maximum concentration of cytoplasmic hamamelitol was 155 mol m−3 and occurred in field‐grown plants. Labelling experiments showed that hamamelitol is slowly synthesized from 14CO2 in leaves of H. helix, but is very long‐lived (estimated t1/2 of 4 years). Together, these data indicate that hamamelitol probably functions during long‐term stress conditions as an osmotically active, compatible solute in plant leaves. We suggest that the signal for enhanced accumulation of hamamelitol during the water stress treatment was initiated by decreased plant growth and increased leaf sucrose hydrolysis.