bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustained mental workload does not affect subsequent sleep intensity
Authors: De Bruin Eveline A. , Beersma Domien G. M. , Daan Serge
Published: March 2003

Mental activity is a neglected factor in sleep research. The few investigations on sleep that manipulate prior mental activity are inconclusive with respect to the possible effects of mental activity on recovery. In the present study, the effects of two levels of mental activity on subsequent sleep were studied. Thirteen male subjects (range 18–28 years) participated in one lightly and two heavily mentally strenuous conditions in a counterbalanced order. Light mental activity included 8 h of relaxed video watching. The second condition consisted of performing computer tasks involving sustained attention, memory, logical thinking and calculations for eight consecutive hours. In the third condition, the same heavy mental workload was interspersed with breaks. Subjectively, the subjects rated the condition with heavy mental activity (without breaks) as mentally more strenuous than the condition with light mental activity. Subjects were significantly less awake shortly after sleep onset in the heavy‐workload condition than in the light‐workload condition. There were no differences between the conditions in any of the other visually scored sleep variables. The total amount of slow wave activity (SWA) and its discharge during the night was not affected by the level of mental activity or by the presence of breaks. These findings fail to support the proposition that SWA reflects a need for sleep that accumulates at a rate depending on mental activity during prior wakefulness.
The effect of an irregular shift system on sleepiness at work in train drivers and railway traffic controllers
Authors: Härmä M. , Sallinen M. , Ranta R. , Mutanen P. , Müller K.
Published: March 2003

Sleepiness and fatigue are frequent problems in railway transportation with occasional monotony and irregular shift schedules. This study aimed at (1) studying the prevalence of severe sleepiness in shifts and (2) examining which shift and sleep‐related factors were associated with the occurrence of severe sleepiness in an irregular shift system. A total of 126 randomly selected male train drivers (Tdrs) and 104 railway traffic controllers (Tcos) were investigated using questionnaires and sleep–wake diaries. A sleep diary was used to collect information on sleepiness at work and sleeping times during the 21 consecutive days of the study. The prevalence of severe sleepiness at work (i.e. Karolinska Sleepiness Scale 7 or higher) was modelled by a logistic regression analysis for repeated measurements (GEE) using different shift schedule related factors and sleep length as explanatory variables. Severe sleepiness was reported in 49% (Tdrs) and 50% (Tcos) of the night shifts and in 20% (Tdrs) and 15% (Tcos) of the morning shifts. The odds ratios showed that the risk for severe sleepiness was 6–14 times higher in the night shift and about twice as high in the morning shift compared with the day shift. Age affected the two occupational samples differently: with Tdrs increased age was associated with an additional 8% reduction of risk for severe sleepiness for each year of age, while the Tcos did not show any age dependency. Shift length increased the risk by 15% for each hour of the shift and main sleep period decreased the risk by 15% for each hour of the main sleep. The risk of severe sleepiness was not consistently related to the time‐off period before the shifts. The results indicate that adjustments for shift timing, length and off‐duty time, in addition to actions aiming at extending the main sleep period, would probably decrease severe sleepiness in railway transportation.
Situational factors affecting sleep paralysis and associated hallucinations: position and timing effects
Authors: Cheyne J. A.
Published: March 2003

Sleep paralysis (SP) entails a period of paralysis upon waking or falling asleep and is often accompanied by terrifying hallucinations. Two situational conditions for sleep paralysis, body position (supine, prone, and left or right lateral decubitus) and timing (beginning, middle, or end of sleep), were investigated in two studies involving 6730 subjects, including 4699 SP experients. A greater number of individuals reported SP in the supine position than all other positions combined. The supine position was also 3–4 times more common during SP than when normally falling asleep. The supine position during SP was reported to be more prevalent at the middle and end of sleep than at the beginning suggesting that the SP episodes at the later times might arise from brief microarousals during REM, possibly induced by apnea. Reported frequency of SP was also greater among those consistently reporting episodes at the beginning and middle of sleep than among those reporting episodes when waking up at the end of sleep. The effects of position and timing of SP on the nature of hallucinations that accompany SP were also examined. Modest effects were found for SP timing, but not body position, and the reported intensity of hallucinations and fear during SP. Thus, body position and timing of SP episodes appear to affect both the incidence and, to a lesser extent, the quality of the SP experience.
Towards an understanding of self‐reports of sleep
Authors: Gehrman Philip , Matt Georg E. , Turingan Maria , Dinh Quyen , Ancoli‐Israel Sonia
Published: March 2003

Sleep research has made extensive use of self‐report measures relying on a response format that requires respondents to provide single, specific numerical estimates. The cognitive processes involved in storing and retrieving sleep‐related information allow only approximate numeric estimates of sleep behavior. Based on a fuzzy set model of survey responses, a response format is proposed to better capture the inherent vagueness of quantitative estimates of sleep behavior. Ninety‐three adults (mean age 29.3 years) participated in two interviews, 1 month apart, consisting of questions about health‐related behaviors. Questions were asked in both traditional point estimate and fuzzy response formats. A subset of questions was repeated at the end of each interview to examine test–retest reliability. Subjects filled out daily diaries each morning during the month between interviews. Quantitative estimates of usual sleep behavior were found to be highly reliable. Point estimates differed significantly from fuzzy boundary estimates. Differences between lower and upper boundary estimates indicated substantial ranges in estimates of usual sleep: total sleep time (6–8.2 h), sleep latency (26–44 min), bed time (11:25 PM–12:56 AM) and waking time (7:24–8:39 AM). Mean diary‐recorded bed and waking times fell between the lower and upper boundary estimates in more than 53% of cases, and between the lower and upper extreme estimates in more than 92% of cases. Fuzzy response formats provide an opportunity to report more completely what can be recalled about sleep behavior. They also provide a useful framework for better understand the meaning of traditional point estimate formats.
Insomnia and global sleep dissatisfaction in Finland
Authors: Ohayon Maurice M. , Partinen Markku
Published: March 2003

The purpose of this study is to assess the prevalence of insomnia symptoms and diagnoses in the general population of Finland. A total of 982 participants, aged 18 years or older and representative of the general population of Finland, were interviewed by telephone using the Sleep‐EVAL system. The participation rate was 78%. The questionnaire included the assessment of sleep habits, insomnia symptomatology according to Diagnostic and Statistical Manual of Mental Disorders‐IV (DSM‐IV) and International Classification of Sleep Disorders (ICSD), associated and sleep/mental disorders and daytime consequences. The overall prevalence of insomnia symptoms occurring at least three nights per week was 37.6%. Difficulty initiating sleep were mentioned by 11.9% of the sample, difficulty maintaining sleep by 31.6%, early morning awakenings by 11.0% and non‐restorative sleep by 7.9% of the sample. Global dissatisfaction with sleep was found in 11.9% of the sample. Daytime consequences (fatigue, mood changes, cognitive difficulties or daytime sleepiness) were reported by 39.9% of participants with insomnia symptoms and 87.6% of those with sleep dissatisfaction. A deterioration of sleep in summer or winter was associated with more complaints of sleep dissatisfaction. Prevalence of any DSM‐IV insomnia diagnosis was 11.7%. More specifically, DSM‐IV diagnosis of primary insomnia had a prevalence of 1.6% and DSM‐IV diagnosis of insomnia related to another mental disorder was at 2.1%. Insomnia was a symptom of another sleep disorder in about 16% of cases and of a mental disorder in about 17% of cases. As reported in other Nordic studies, sleep quality was worse in summer. Insomnia symptomatology was common and was reported by more than a third of Finnish participants. Compared with other European countries studied with the same methodology (France, the UK, Germany, and Italy), the prevalence of DSM‐IV insomnia diagnosis was 1.5 to two times higher in Finland.
The ontogeny of mammalian sleep: a reappraisal of alternative hypotheses
Authors: Frank Marcos G. , Heller H. Craig
Published: March 2003

Newborn mammals spend as much as 90% or more of their time in a sleep state characterized by frequent twitches, rapid eye movements (REMs), and irregular respiratory cycles. These motor and respiratory patterns resemble the phasic motor/respiratory components of adult REM sleep, and as a consequence, this sleep state is traditionally viewed as an immature form of REM sleep. An alternative view is that a significant portion of what has been called REM sleep in these species is a form of spontaneous activity typical of the immature nervous system. In this review, we compare and contrast these two opposing views about the ontogenetic origins of REM sleep, and review the evidence most often cited to support the idea that REM sleep is present in newborn altricial mammals. Critical review of this evidence indicates that REM sleep may not be present at birth in these species; rather, it appears that all mammals early in development exhibit spontaneous, dissociated activity that progressively becomes organized into the distinct states of REM and non‐rapid eye movement sleep.
The 7th International Congress of EAVPT
Authors: Anadón A.
Published: March 2003

Abstract here
Ovarian function suppression with a GnRH analogue: d‐ser(But[t])[6]‐Arzgly[10]‐LHRH (Goserelin) in hormone dependent canine mammary cancer
Authors: Lombardi  , Florio  , Pagnini  , Crispino  , Avallone
Published: March 2003

Hormones and hormone level modifying substances have long been used to treat hormone‐dependent tumours in humans. Recently, attempts have been made to use hormone manipulation regimens for the treatment of these tumours in veterinary medicine. The aim of the present study was to evaluate the activity of the luteinizing hormone‐releasing hormone (LHRH)‐agonist, d‐ser(But[t])[6]‐Azgly[10]‐LHRH (Goserelin) in hormone‐dependent mammary cancer in dogs. Eighteen female dogs with hormone‐dependent mammary cancer (T2‐T4, N0, M0 according to TNM clinical staging classification) were selected and allocated into two groups: nine dogs not treated with Goserelin (Group 1) referred to as control; and nine dogs treated with 60 μg/kg depot Goserelin every 21 days for 12 months (Group 2). Goserelin treatment decreased circulating levels of oestradiol and progesterone and reduced the size of mammary tumours; all the animals showed objective response (OR) to treatment after 3 months, and the relapse‐free survival after 2 years was 88%. Haematology and blood chemistry parameters, measured every month from the beginning of treatment, as well as physical examination, showed that the drug was without toxic effects. This suggests that, at the dose administered, Goserelin blocks the hypothalamus‐pituitary‐ovary axis, and consequently can be useful to treat hormone‐dependent mammary tumours in female dogs.
Loperamide‐induced enhancement of moxidectin availability in cattle
Authors: LIFSCHITZ A. , VIRKEL G. , SALLOVITZ J. , IMPERIALE F. , PIS A. , LANUSSE C.
Published: March 2003

Moxidectin (MXD) is a milbemycin endectocide compound active at extremely low dosages against a wide variety of nematode and arthropod parasites. Different pharmacological approaches are currently being tested to delay the bile‐faecal elimination and to obtain increased systemic availability for endectocide molecules in ruminants. Loperamide (LPM) is an opioid derivative, whose main pharmacological action is to abolish intestinal propulsive peristaltic waves. The influence of LPM on the pattern of faecal excretion of MXD and on its plasma disposition following intravenous (i.v.) and subcutaneous (s.c.) administrations to cattle was evaluated in the current work. Parasite‐free calves were treated with MXD given either alone at 200 μg/kg by i.v. (Experiment 1) and s.c. (Experiment 2) administrations or coadministered with LPM subcutaneously injected at 0.4 mg/kg. Blood and faecal samples were collected over a period of 20 (Experiment 1) and 40 (Experiment 2) days post‐treatment. The recovered plasma and faecal samples were extracted and analysed by high‐performance liquid chromatography (HPLC) using fluorescence detection. Significantly higher MXD plasma concentrations were obtained after the coadministration of MXD + LPM compared with treatments with MXD alone by both routes. The higher MXD plasma concentration profiles measured after the coadministration with LPM accounted for the significantly higher AUC values obtained following the i.v. (> 46%) and s.c. (> 38%) treatments. A reduced MXD body clearance was observed in the presence of LPM. The appearance of MXD in faeces was significantly delayed after the i.v. and s.c. coadministrations of MXD with LPM (T1/2app=5.87 and 10.6 h, respectively) than that observed after the treatment with MXD alone (T1/2app=3.48 and 5.12 h). A delayed MXD peak concentration in faeces collected from MXD + LPM‐treated animals compared with those receiving MXD alone, was observed. The delayed intestinal transit time caused by LPM and a potential competition between MXD and LPM for theP‐glycoprotein‐mediated bile/intestinal secretion processes, may account for the enhanced MXD systemic availability measured in cattle in the current work.
In subjects with antibody to hepatitis C virus a high serum level of interleukin‐2 soluble receptor suggests activity of liver disease
Authors: Gessoni G. , Valverde S. , Giacomini A. , Antico F. , Manoni F.
Published: March 2003

The hepatitis C virus (HCV) is an RNA virus without apparent cytopathic effects, and hepatocellular damage in chronic infection is generally believed to be immune‐mediated by cytotoxic T lymphocytes. Activated T cells release the soluble form of the interleukin‐2 (IL‐2) receptor (sIL‐2R) and its concentration is correlated with the degree of lymphocyte activation. We measured sIL‐2R in 69 subjects: 24 healthy repeat blood donors (group I), 17 HCV carriers without liver damage (group II) and 28 patients with HCV‐related chronic active hepatitis (group III). There was no significant difference between sIL‐2R levels in patients of group I (36.5±14.6Uml–1) and group II (46.8±17.4Uml–1), and the levels for both of these groups were significantly lower than those observed in the patients with active HCV, group III (176.9±59.5Uml–1). Hence, among HCV‐infected subjects (HCV RNA positive) with persistently normal alanine aminotransferase (ALT) levels, the plasma levels of sIL‐2R are normal, but, in patients (HCV RNA positive) with HCV‐related chronic active hepatitis there are increased plasma levels of sIL‐2R. We conclude that in HCV infection high levels of sIL‐2R are related to activity of the disease rather than to virus replication. In patients with HCV‐related chronic liver disease, the sIL‐2R concentration may be a useful marker of disease activity.
Prevalence and determinants of hepatitis A virus exposure among prison entrants in Queensland, Australia: implications for public health control
Authors: Whiteman D. , McCall B. , Falconer A.
Published: March 2003

In September 1997, a multicentre outbreak of hepatitis A virus (HAV) infection occurred in the Queensland prison system following a prolonged community‐based HAV epidemic among illicit drug users. As part of the public health response, a cross‐sectional survey was undertaken to estimate the seroprevalence of, and identify the determinants for, recent and past HAV infection among the incoming male prisoner population. Exposure data were collected through face‐to‐face interviews with 214 consenting inmates, whose sera were screened for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to HAV. Overall, 81 (37.9%) inmates were HAV‐IgG seropositive, and four inmates were HAV‐IgM seropositive, HAV‐IgG seropositivity was strongly associated with year of birth (age) (Ptrend<0.0001), being born outside Australia (relative risk (RR) 1.9, 95% CI 1.4–2.7) and being of a non‐English speaking background (RR 2.5, 95% CI 1.7–3.7). Lifestyle exposures (such as occupation, overseas travel and illict drug use) were not associated with an increased risk of HAV‐IgG seropositivity. In contrast, all four HAV‐IgM seropositive inmates were English‐speaking, Australian‐born males who used illicit drugs. These findings suggest that the risk factors for recent and past HAV infections among prisoners differ, with implications for HAV control in correctional settings. Strategies for HAV prevention, including routine screening of inmates and vaccination of susceptibles, are considered in the context of current models of disease transmission.
Degree and distribution of variability in the 5' untranslated, E1, E2/NS1 and NS5 regions of the hepatitis C virus (HCV)
Authors: Vizmanos J. L. , González‐Navarro C. J. , Novo F. J. , Civeira M. P. , Prieto J. , Gullón A. , García‐Delgado M.
Published: March 2003

Hepatitis C virus (HCV) shows a high degree of variability resulting in many different variants. In this work we described the variability of several subgenomic fragments from the 5' untranslated region (5'‐UTR) and E1, E2/NS1 and NS5 regions comparing, for every position, all the sequences published in GenBank® v. 88 (July 1995) as well as new sequences obtained in this work. Variability was determined in two ways. First, we analysed the degree and type of substitutions found in these regions. Second, we defined the most variable and conserved segments in each region and compared our prediction with previous studies. Our results confirm that HCV variability changes along the different regions. Although we found four variable domains in the 5'‐UTR, this region was the only one to contain conserved domains. Envelope (E1, E2/NS1) and NS5 regions showed high variability throughout; however, we were able to define six and three hypervariable domains, respectively. The degree and distribution of variability established in this work is supported by the high number of sequences and the different types included in the study. Knowledge of how variability is distributed along the different regions of the HCV genome could be of use in the design of new diagnostic and therapeutic strategies against HCV infection.
Prevalence of hepatitis B and C markers in volunteer blood donors in Crete. A 5‐year study
Authors: Koulentaki M. , Spanoudakis S. , Kantidaki E. , Drandakis P. , Tzagarakis N. , Biziagos E. , Moschandrea J. , Kouroumalis E. A.
Published: March 2003

Greece is a country with an intermediate prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Crete, the third‐largest island of the Mediterranean sea, has a different prevalence of viral hepatitis. One‐eighth of the total island population, of 550000, was included in a 5‐year study of blood donors from three out of four blood banks, serving three out of four prefectures of the island. Markers for HBV and HCV were studied and evaluated according to geographical area, gender and age of donor. A total of 65219 blood donors were studied. A greater number of males than females were hepatitis B surface antigen (HBsAg) positive (0.41%vs 0.28%, respectively) with a peak at a younger age for males and older age for females. Males are more frequently exposed to HBV and become carriers more often than females. For HCV, an opposite gender trend was found, females being infected more frequently (0.49%) than males (0.37%). Statistical differences were found among geographical areas of the island. Hence, Crete is an area of low endemicity for HBsAg in blood donors. The HCV infectivity is more similar to Northern Europe than to other neighbouring countries. Differences in geographical distribution within the island and during different years indicate the need for extended epidemiological surveys for valid results.
Mutations in the hepatitis B virus polymerase gene associated with antiviral treatment for hepatitis B
Authors: Hussain M. , Lok A. S. F.
Published: March 2003

Significant advances have been made, during the last 5 years, in the treatment of chronic hepatitis B. Several new antiviral agents: lamivudine, famciclovir, lobucavir and adefovir, have been shown to be safe and effective in inhibiting hepatitis B virus (HBV) replication. These compounds can be administered orally and are well tolerated. However, virus clearance is uncommon after short courses (<6 months) of therapy. Lamivudine and famciclovir have been evaluated in Phase III clinical trials in patients with chronic hepatitis B as well as in liver transplant recipients. Unfortunately, drug‐resistant mutants involving the HBV polymerase gene, leading to breakthrough infection, have been reported in some patients who have received long courses (≥ 12 months) of treatment. The incidence, clinical outcome and biological significance of these mutants will be reviewed.
Semiquantitative assessment of IgM antibody to hepatitis B core antigen and prediction of the severity of chronic hepatitis B
Authors: Colloredo G. , Bellati G. , Sonzogni A. , Zavaglia C. , Fracassetti O. , Leandro G. , Ghislandi R. , Minola E. , Ideo G.
Published: March 2003

Controversial results have been reported concerning the correlation between serum levels of IgM antibodies to hepatitis B core antigen (IgM HBcAb) and the histological activity of chronic hepatitis B. In this study, paired serum samples and liver biopsies were collected from 200 consecutive chronic hepatitis B patients (mean age 39.2 ± 0.8 years; M:F 154:46; 41 hepatitis B e antigen (HBeAg) positive) and tested for IgM HBcAb using a semiquantitative highly sensitive assay (IMx CORE‐M®). The severity of liver disease was assessed by the Ishak score, grading the necroinflammatory activity (by using the histology activity index, HAI) and staging the fibrosis. The index values of IgM HBcAb were significantly different among patients with mild (HAI ≤ 6), moderate (HAI 7–12) and severe (HAI ≥ 13) necroinflammatory activity but the stage of fibrosis was unrelated to the IgM HBcAb. According to the index value of IgM HBcAb, we selected three groups of patients: Group A included 36 patients with an index value below 0.200; Group B, 99 patients with an index value between 0.200 and 0.500; and Group C, 65 patients with an index value over 0.500. The mean HAI grading in Group A was 5.3 ± 0.4, in Group B it was 7.4 ± 0.3 and in Group C it was 8.9 ± 0.4 (f = 16.5, P < 0.0001). A mild HAI grading was observed in 77.8% of Group A, in 47.5% of Group B and in 23.1% of Group C patients; conversely, severe grading was detected in 0% of Group A, in 11.1% of Group B and in 18.5% of Group C patients (P < 0.0001). An index value of IgM HBcAb below 0.200 was 75% predictive of a mild necroinflammatory activity (29% sensitivity and 91.6% specificity) and ruled out a severe activity. Therefore, the quantitative assessment of IgM HBcAb appears to be a useful clinical tool in the prediction of the necroinflammatory activity of chronic hepatitis B. A serum index value of IgM HBcAb consistently below 0.200 could be considered a surrogate marker of remission of hepatitis B virus‐induced liver disease.
Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection?
Authors: Mayerat C. , Mantegani A. , Frei P. C.
Published: March 2003

Between 5 and 10% of adults infected with the hepatitis B virus (HBV) develop a chronic infection lasting longer than 6 months, which may lead to advanced liver disease. HBV can be classified into six genotypic families: A, B, C, D, E and F, but only genotypes A and D are significantly represented in western Europe, where they account for some 90% of cases of infection with HBV. In the present study, we investigated a possible association between HBV genotype A or D and clinical outcome of the infection. We compared the prevalence of these genotypes in a group of patients with chronic active hepatitis to that of a group with acute resolving hepatitis. In patients with chronic active hepatitis, genotype A was found in 28 of 35 patients and genotype D in only four. The remaining three patients were infected with genotype non‐A, non‐D. In contrast, genotype D was found in 24 of 30 patients with acute hepatitis, whilst genotype A was found in only three patients of this group. Three were infected with genotype non‐A, non‐D. Our results show a clear association between genotype A and chronic outcome (Ficher’s exact test: two‐sided P‐value, P < 0.0001). They suggest that HBV genotypes may play a role in the virus–host relationship. Possible mechanisms for such a role are discussed.
Gene therapy of viral hepatitis and hepatocellular carcinoma
Authors: Ruiz J. , Qian C. , Drozdzik M. , Prieto J.
Published: March 2003

Gene therapy represents an attractive approach to treat a great variety of diseases, both inherited and acquired, and it is moving slowly from a proof‐of‐principle phase to a wide application in most medical fields. Liver cancer and viral hepatitis are natural targets for this new therapeutic alternative due to the lack of success of conventional antitumoral and antiviral treatments and the ominous prognosis related with liver tumours. Gene therapy for viral hepatitis is aimed to boost the patient immune response against viral antigens or to make cells resistant to infection by blocking the viral life cycle. Gene transfer techniques applied to the treatment of hepatocellular carcinoma include drug sensitization by suicide genes, genetic immunotherapy, normal tissue protection by transfer of the multidrug resistance gene, replacement of tumour suppressor genes, inhibition of oncogenes and modifications of the biology of the tumour (antiangiogenesis). However, major advances in our understanding of the regulation of gene expression, design of the expression cassettes and development of more efficient gene transfer vectors are mandatory before gene therapy can become a widely used therapeutic modality.
Hepatitis C virus RNA in kidney biopsies from infected patients with renal diseases
Authors: Rodríguez‐Iñigo  , Casqueiro  , Bartolomé  , Barat  , Caramelo  , Ortiz  , Albalate  , Oliva  , Manzano  , Carreño
Published: March 2003

Hepatitis C virus (HCV) infection has been associated with several renal pathologies, including membranoproliferative and membranous glomerulonephritis. Although the presence of HCV proteins has been reported, there are no data concerning detection of the viral RNA in renal cells from HCV‐infected patients with kidney disease. In this report we analysed, by in situ hybridization, the presence of HCV RNA in renal biopsies from 10 patients who were positive for antibodies to HCV (anti‐HCV) and serum HCV RNA positive, and from four patients without HCV infection, with different renal disease. HCV RNA was detected in the renal biopsies from all of the 10 HCV‐infected patients. Hybridization signals were detected in the tubular and capillary endothelial cells. No hybridization signals were found in the renal biopsies of the four anti‐HCV‐negative patients. In conclusion, our results demonstrate that HCV RNA is common in kidney cells of patients with renal diseases who are infected with HCV. The presence of HCV RNA is not necessarily associated with a pathogenetic consequence.
A randomized controlled trial of kurorinone versus interferon‐α2a treatment in patients with chronic hepatitis B
Authors: Chen  , Guo  , Liu
Published: March 2003

It has recently been shown that a Chinese traditional medicine, kurorinone, extracted from Sophora Flavescens Ait, possesses antiviral properties. We evaluated the efficacy and safety of kurorinone treatment in patients with chronic hepatitis B. Ninety‐four patients with abnormal alanine transaminase (ALT) levels and hepatitis B e antigen (HBeAg) and/or hepatitis B virus (HBV) DNA‐positivity were randomly assigned to receive either kurorinone 400 mg daily (45 patients) or 3 million units (MU) of interferon‐α (IFN‐α) (49 patients, daily for 1 month, every other day for 2 months) for 3 months. Patients were followed‐up for 12 months. At baseline, both groups were comparable regarding age, gender and serological parameters. At the end of treatment, complete response (defined as ALT normalization and HBeAg and/or HBV DNA loss) occurred in 50% of the kurorinone group and in 61.3% of the IFN‐α‐treated group (P > NS). At the end of the 12‐month follow‐up period, a complete response (sustained response) occurred in 26.7–36.7% of kurorinone‐treated patients with moderate or mild liver damage and in 44.4–46.7% of IFN‐α‐treated patients with similar liver injury. In kurorinone‐ as well as in IFN‐α‐treated patients, there was no statistical significant difference with respect to complete response rates between HBeAg‐positive and hepatitis B e antibody‐positive subgroups. Kurorinone had no untoward side‐effects except for local pain at injection sites. The results of this trial suggest that kurorinone is able to inhibit HBV replication and improve disease remission in patients with chronic hepatitis B.
Impact of chronic hepatitis B and interferon‐α therapy on growth of children
Authors: Comanor L. , Minor J. , Conjeevaram H. S. , Roberts E. A. , Alvarez F. , Bern E. M. , Goyens P. , Rosenthal P. , Lachaux A. , Shelton M. , Sarles J. , Sokal E. M.
Published: March 2003

Interferon‐α (IFN) has been approved as treatment for children with chronic hepatitis B (CHB). The aims of this study were to assess the impact on children’s growth of the disease itself and of IFN treatment. The growth of 142 children with CHB (70 IFN‐treated, 72 untreated) was monitored for a minimum of one year. Regression analysis models were used to determine which of the variables most affected children’s growth. After adjusting for racial differences, the population of 142 children with CHB had a mean baseline height for age percentile of 39 and a mean baseline weight for age percentile of 38, which were significantly different (P < 0.0001) from the 50th percentiles of their respective reference populations. The height for age Z score of untreated children was inversely correlated with serum hepatitis B virus DNA and aspartate aminotransferase levels, and the weight for age Z score was inversely correlated with serum hepatitis B virus DNA levels. While undergoing IFN therapy, children displayed a ‘U‐shaped’ growth pattern, such that height for age and weight for age Z scores at 3 or 6 months were lower than scores at baseline or 12 months. In this study the average child with CHB showed compromised growth even in the absence of IFN therapy. During IFN therapy, children’s growth was temporarily disrupted.
Prevalence and genotype distribution of TT virus in various specimen types from thalassaemic patients
Authors: Chan P. K. S. , Chik K.‐W. , Li C.‐K. , Tang N. L. S. , Ming M. S. K. , Cheung J. L. K. , Ng K.‐C. , Yuen P. M. P. , Cheng A. F.
Published: March 2003

Peripheral blood mononuclear cells (PBMC), plasma, saliva and urine samples were collected from 50 thalassaemic patients for TT virus (TTV) detection by two sets of PCR. The set B nested PCR was more sensitive than the widely used NG hemi‐nested PCR with TTV positive rates ≈ PBMC: 98% vs. 70%; plasma: 92% vs. 66%; saliva: 62% vs. 22%; urine: 22% vs. 6%. All 50 patients had TTV detected in one or more specimens, with 16% of patients being positive in all four specimen types: 40% positive in PBMC, plasma and saliva; 30% positive in PBMC and plasma. In 82 NG hemi‐nested PCR‐positive samples TTV genotype was identified, 68.3% had a single genotype, 25.6% had multiple genotypes and 6.1% were uncharacterized. The positive rates for genotypes by specimen were: G1 (36/82), G2 (49/82), G3 (2/82), G4 (7/82), G5 (1/82) and G6 (3/82). Among the 42 patients for whom the genotype was examined, 42.9% had single‐type infection, 45.2% had co‐infections and 11.9% had uncharacterized genotypes. Sixteen of them had TTV detected both in PBMC and plasma with seven having identical genotypes in both samples. Eight patients had TTV detected in PBMC, plasma and saliva; two of them harboured identical genotypes in all three samples. The results indicate that, apart from hepatocytes, PBMC is a major cell type for TTV infection occurs. Shedding of TTV in urine and saliva is common and may have a significant role in nonblood‐borne transmission among the general population. TTV‐infected patients often harbour multiple genotypes suggesting infection with one genotype does not necessarily confer protection against the others. No correlation between TTV infection and liver dysfunction was observed.
Cell transformation induced by hepatitis C virus NS3 serine protease
Authors: Zemel R. , Gerechet S. , Greif H. , Bachmatove L. , Birk Y. , Golan‐Goldhirsh A. , Kunin M. , Berdichevsky Y. , Benhar I. , Tur‐Kaspa R.
Published: March 2003

Persistent infection with hepatitis C virus (HCV) may lead to hepatocellular carcinoma (HCC). It has been suggested that HCV‐encoded proteins are directly involved in the tumorigenic process. The HCV nonstructural protein NS3 has been identified as a virus‐encoded serine protease. To study whether HCV NS3 has oncogenic activity, nontumorigenic rat fibroblast (RF) cells were stably transfected with an expression vector containing cDNA for the NS3 serine protease (nucleotides 3356–4080). The NS3 serine protease activity was determined in the transfected cells. The transfected cells grew rapidly and proliferated serum independently, lost contact inhibition, grew anchorage independently in soft agar and induced significant tumour formation in nude mice. Cells transfected with an expression vector containing a mutated NS3 serine protease (serine 139 to alanine at the catalytic site) showed no transforming abilities; their growth was dependent on serum and they did not grow anchorage independently in soft agar. Moreover, cells transfected with the NS3 serine protease and treated with the chymotrypsin inhibitors TPCK and PMSF (a serine protease inhibitor) lost their transforming feature. These results suggest that the NS3 serine protease of HCV is involved in cell transformation and that the ability to transform requires an active enzyme.
Hepatitis C: an epidemiological review
Authors: Memon M. I. , Memon M. A.
Published: March 2003

The aim of the study was to analyse the current literature regarding the mode of transmission of HCV and its global prevalence in different groups of people. A systematic review of the literature on the epidemiology of hepatitis C from 1991 to 2000 using computerized bibliographic databases which include Medline, Current Content and Embase. The prevalence of hepatitis C virus (HCV) varies tremendously in different parts of the world, with the highest incidence in the Eastern parts of the globe compared with the Western parts. Furthermore, certain groups of individuals such as intravenous drug users are at increased risk of acquiring this disease irrespective of the geographical location. Although the main route of transmission is via contaminated blood, curiously enough in up to 50% of the cases no recognizable transmission factor/route could be identified. Therefore, a number of other routes of transmission such as sexual or household exposure to infected contacts have been investigated with conflicting results. Hepatitis C infection is an important public health issue globally. Better understanding of routes of transmission will help to combat the spread of disease. In order to prevent a world wide epidemic of this disease, urgent measures are required to (i) develop a strategy to inform and educate the public regarding this disease and (ii) expedite the efforts to develop a vaccine.
A single nucleotide polymorphism of the low molecular mass polypeptide 7 gene influences the interferon response in patients with chronic hepatitis C
Authors: Sugimoto Y. , Kuzushita N. , Takehara T. , Kanto T. , Tatsumi T. , Miyagi T. , Jinushi M. , Ohkawa K. , Horimoto M. , Kasahara A. , Hori M. , Sasaki Y. , Hayashi N.
Published: March 2003

summary. Transporter associated with antigen processing (TAP) and low molecular mass polypeptides (LMP) play crucial roles in the human leukocyte antigen (HLA) class I‐restricted antigen presenting systems. This study was performed to elucidate whether these antigen‐presenting gene polymorphisms could influence the response to interferon (IFN) treatment in patients with chronic hepatitis C. Polymorphisms of TAP and LMP genes in 175 hepatitis C virus (HCV) patients were determined by polymerase chain reaction‐restriction fragment length polymorphism. The frequencies of these genes were compared between sustained‐responders (n=49) and nonresponders (n=126), classified by biochemical and virological responses to IFN. The distributions of TAP1*, TAP2*, and LMP2 genes between sustained‐responders and nonresponders did not differ. However, LMP7‐K gene frequency in sustained‐responders was higher than that in nonresponders [odds ratio 2.3 (95% confidence interval 1.1–4.6); 16%vs 7.9%]. Multivariate analysis revealed that LMP7‐K and HCV‐RNA quantity were independent factors influencing the outcome of IFN therapy [4.5 (1.4–14); P=0.011, 0.40 (0.24–0.65); P=0.0003, respectively]. Furthermore, among patients with a low viral load (≤ 2.0 Meq/mL), the LMP7‐K positive patients had an even higher ratio of sustained response compared to those without LMP7‐K [5.9 (1.6–22); 82%vs 44%; P=0.0062]. These findings suggest that a single nucleotide polymorphism of LMP7 gene is one of the important host factors which independently influence the response to IFN in patients with chronic hepatitis C.
Early viral clearance and sustained response in chronic hepatitis C: a controlled trial of interferon and ribavirin after high‐dose interferon induction
Authors: Di Marco V. , Ferraro D. , Almasio P. , Vaccaro A. , Parisi P. , Cappello M. , Cino N. , Di Stefano R. , Craxì Antonio
Published: March 2003

summary. High‐dose induction with α‐interferon induces early viral clearance of hepatitis C and combined with ribavirin enhances sustained response. We assess whether adding ribavirin after viral clearance obtained by α‐interferon induction increased the rate of viral eradication.Forty‐one naïve patients with chronic hepatitis C were randomised to receive, after 4 weeks of 10 mU daily of α‐interferon (induction), 3 mU daily for 22 weeks and 3 mU thrice weekly for 26 weeks of either interferon alone (monotherapy) or interferon plus 1000–1200 mg daily of ribavirin (combination therapy). At the end of the induction phase, 23 (56%) subjects had cleared HCV‐RNA. During therapy, breakthrough was observed in four patients on monotherapy, but never in patients on combination therapy. The rate of clearance of HCV‐RNA was different between monotherapy and combination therapy at the end of treatment (40% vs. 76.1%, P=0.02) and at the end of follow‐up (5% vs. 57.1%, P=0.001). Twelve of the 23 patients who cleared HCV‐RNA during induction, but only one of the 18 still HCV‐RNA‐positive after 4 weeks of therapy, had a sustained response (52.2% vs. 5.6%, P=0.001). Clearance of HCV‐RNA at 1 week had a high positive predictive value for sustained response in combination therapy (PPV=0.75), but not in monotherapy (PPV=0.33). Induction with high daily doses of α‐interferon obtains suppression of hepatitis C in more than half of patients, but ribavirin is needed to maintain a sustained response. The rate of sustained response is a function of the time to HCV‐RNA clearance. In patients not responding to induction therapy addition of ribavirin does not obtain a sustained virological response.
Characterization of nuclease‐resistant ribozymes directed against hepatitis B virus RNA*
Authors: Morrissey D. V. , Lee P. A. , Johnson D. A. , Overly S. L. , McSwiggen J. A. , Beigelman L. , Mokler V. R. , Maloney L. , Vargeese C. , Bowman K. , O'Brien J. T. , Shaffer C. S. , Conrad A. , Schmid P. , Morrey J. D. , Macejak D. G. , Pavco P. A. , Blatt L. M.
Published: March 2003

summary. Hepatitis B virus (HBV) is responsible for > 350 million cases of chronic hepatitis B worldwide and 1.2 million deaths each year. To explore the use of ribozymes as a novel therapy for HBV infection, nuclease‐resistant ribozymes that target highly conserved regions of HBV RNA were screened in cell culture. These synthetic ribozymes have the potential to cleave all four major HBV RNA transcripts and to block the HBV lifecycle by cleavage of the pregenomic RNA. A number of the screened ribozymes demonstrate activity in cell culture systems, as measured by decreased levels of HBV surface antigen, HBV e antigen and HBV DNA. In addition, a lead anti‐HBV ribozyme maintains activity against a lamivudine‐resistant HBV variant in cell culture. Treatment of HBV transgenic mice with lead anti‐HBV ribozymes significantly reduced viraemia compared with saline‐treated animals and was as effective as treatment with lamivudine. In conclusion, the therapeutic use of a ribozyme alone or in combination with current therapies (lamivudine or interferons) may lead to improved HBV therapy.
Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy*
Authors: Khuroo M. S. , Kamili S.
Published: March 2003

summary. Hepatitis E causes large‐scale epidemics in endemic areas. The disease, during epidemics, has increased incidence and severity in pregnant women. Sporadic acute viral hepatitis (AVH) is common in endemic areas. The relationship of sporadic AVH and pregnancy has not been well studied. Over a 3‐year period we prospectively studied 76 pregnant women and 337 non‐pregnant women of childbearing age with sporadic acute viral hepatitis for aetiology, clinical course and outcome of disease. The aetiology in sporadic AVH was hepatitis A virus (HAV) in six (1.5%), hepatitis B virus (HBV) in 62 (15%), hepatitis C virus (HCV) in seven (1.7%), hepatitis D virus (HDV) co‐infection in six (1.5%), hepatitis E virus (HEV) in 205 (49.6%), and hepatitis non‐A‐to‐E (HNAE) in 127 (30.7%). Sixty‐five (85.5%) pregnant women and 140 (41.5%) nonpregnant women had hepatitis E. The proportion of pregnant women was 31.7% in HEV group and 5.3% in non‐HEV group [P < 0.001; OR=8.3 (95%C1 4.2–16.3)]. The prevalence of HEV in pregnant women in first trimester (76.9%), second trimester (88.9%), third trimester (83.8%) and puerperium (100%) did not differ significantly (P=0.09). Forty‐seven (61.8%) of the 76 pregnant women developed fulminant hepatic failure (FHF), 69.2% in HEV group and 10% in non‐HEV group (P < 0.001). Thirty‐four (10.1%) nonpregnant women developed fulminant hepatic failure, 10% in HEV group and 9.7% in non‐HEV group (P=0.86). FHF had occurred in four (40%) of 10 patients with HE in first trimester as against 41 (74.5%) of 55 patients in second trimester and beyond (P=0.015). Amongst the major complications of fulminant hepatic failure, cerebral oedema (53.2%) and disseminated intravascular coagulation (21.3%) occurred more often in pregnant women than in nonpregnant women (29.4% and 2.8%; P=0.03 and 0.016, respectively) while infections occurred more often in nonpregnant women (36.1%) than in pregnant women (10.6%; P=0.003). Fifty (61.7%) patients with FHF died [25 (53.2%) pregnant women and 25 (69.5%) nonpregnant women (P=0.06)]. Cerebral oedema and HEV aetiology were independent variables of survival in patients with FHF. Patients with cerebral oedema had worse prognosis and patients with HEV aetiology had best chances of survival. Hence HEV was the most common cause of sporadic AVH in this endemic area. High proportion of pregnant women and increased severity of disease in pregnancy were limited to patients with hepatitis E. Sporadic AVH caused by agents other than HEV did not show any special predilection to or increased severity in pregnancy. FHF in pregnant women caused by HEV was an explosive disease with short pre‐ encephalopathy period, rapid development of cerebral oedema and high occurrence of disseminated intravascular coagulation and may represent a severe manifestation of a Schwartzmann‐like phenomenon.
The safety and tolerability of daily infergen plus ribavirin in the treatment of naíïve chronic hepatitis C patients
Authors: Pockros P. J. , Reindollar R. , McHutchinson J. , Reddy R. , Wright T. , Boyd D.G. , Wilkes L.B.
Published: March 2003

summary.  The treatment of chronic hepatitis C patients was enhanced when the combination of interferon alfa‐2b and ribavirin was shown to be safe and more effective than interferon monotherapy. To date, no published reports have addressed the use of consensus interferon (CIFN) when combined with ribavirin. We conducted a pilot study to compare the safety and tolerability of daily CIFN plus ribavirin to CIFN monotherapy for the initial treatment of chronic hepatitis C patients. Forty subjects were randomized to two treatment groups; CIFN 9 μg daily, or CIFN 9 μg daily plus ribavirin 1000 or 1200 mg daily. All subjects received 48 weeks of therapy except for nongenotype 1 subjects in the combination treatment group who received only 24 weeks of therapy. The results show that at baseline, age, gender, risk factors, race, RNA titres, and liver histology were not different between the two groups. The proportion of subjects with genotype 1 infection was 50% (10/20) and 55% (11/20) for the monotherapy and combination therapy groups, respectively. Fifty (10/20) and sixty‐five (13/20) per cent of subjects in the monotherapy and combination therapy groups exhibited a 2‐log or greater decrease in viral titre at week 12 (P = NS). Using intent‐to‐treat analysis, 20% and 40% of enrolled subjects exhibited a sustained viral response in the monotherapy and combination therapy groups, respectively (P = NS). The proportion of subjects requiring dose reduction was 55% (11/20) and 65% (13/20), respectively. Study discontinuations for any reason were 25% (5/20) and 35% (7/20) for the monotherapy and combination groups, respectively. Discontinuations due to adverse events related to study drug were 20% (4/20) and 25% (5/20), respectively. A total of four serious adverse events occurred, two in each treatment group, only one of which was determined to be study‐drug related. It is concluded that the safety and tolerability profiles of the two treatments were similar suggesting that daily dosing of CIFN may be difficult to tolerate resulting in discontinuation of therapy in a significant proportion of patients. The combination regimen resulted in a trend towards a higher viral response rate than monotherapy treatment. These data suggest that CIFN may be safely combined with ribavirin and may enhance the sustained response rate but is not well tolerated in US patients when given in a daily dosing regimen.