bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate
Authors: ALIABADI F. SHOJAEE , LEES P.
Published: March 2003

Aliabadi, F. S., Lees, P. Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate.J. vet. Pharmacol. Therap.25,161–174.

Marbofloxacin is a fluoroquinolone antimicrobial drug used in cattle for the treatment of respiratory infections. In this investigation the pharmacokinetics (PK) of marbofloxacin were determined after intravenous and intramuscular dosing at a dosage of 2 mg/kg. In addition theex vivopharmacodynamics (PD) of the drug were determined in serum and three types of tissue cage fluid (transudate, inflammatory exudate generated by carrageenan and exudate generated by lipopolysaccharide). Marbofloxacin PK was characterized by a high volume of distribution after dosing by both routes (1.28 L/kg intravenous and 1.25 L/kg intramuscular). Corresponding area under the concentration–time curve (AUC) and elimination half‐life (t½el) values were 9.99 and 10.11 μg h/mL and 4.23 and 4.33 h, respectively. Values ofAUCfor carrageenan‐induced exudate, lipopolysaccharide‐induced exudate and transudate were, respectively, 8.28, 7.83 and 7.75 μg h/mL after intravenous and 8.84, 8.53 and 8.52 μg h/mL after intramuscular dosing. Maximum concentration (Cmax) values were similar for the three tissue cage fluids after intravenous and intramuscular dosing. Forin vivoPK data values ofAUC:minimum inhibitory concentration (MIC) (AUIC) ratio for serum were 250 and 253, respectively, after intravenous and intramuscular dosing of marbofloxacin against a pathogenic strain ofMannheimia haemolytica(MIC=0.04 μg/mL). For all tissue cage fluidsAUICvalues were >194 and >213 after intravenous and intramuscular dosing, andCmax/MICratios were 9 or greater, indicating a likely high level of effectiveness in clinical infections caused byM. haemolyticaofMIC0.04 μg/mL or less. This was confirmed by bothin vitro(serum) andex vivo(serum, exudate and transudate) measurements, which demonstrated a concentration‐dependent killing profile for marbofloxacin againstM. haemolytica. Ex vivo, after 24‐h incubation, virtually all bacteria were killed (<10 cfu/mL) in all samples collected up to 9 h (serum), 24 h (carrageenan‐induced exudate and transudate) and 36 h (lipopolysaccharide‐induced exudate). Application of the sigmoidEmaxequation to theex vivoantibacterial data provided, for serum,AUIC24 hvalues of 37.1 for bacteriostasis, 46.3 for bactericidal activity and 119.6 for elimination of bacteria. These data may be used as a rational basis for setting dosing schedules which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.
In vitro and in vivo pharmacodynamic properties of the fluoroquinolone ibafloxacin
Authors: Coulet M. , Van Borssum Waalkes M. , Cox P. , Lohuis J.
Published: March 2003

The pharmacodynamic properties of a new veterinary fluoroquinolone antimicrobial agent, ibafloxacin, were evaluated. Minimal inhibitory concentrations (MIC), time‐kill kinetics, postantibiotic effect (PAE) and postantibiotic subminimal inhibitory concentration effects (PA‐SME) were determined against pathogenic canine Gram‐negative and Gram‐positive bacterial isolates from dermal, respiratory and urinary tract infections. The synergistic interactions between ibafloxacin and its main metabolite, 8‐hydroxy‐ibafloxacin were investigated. Finally, the efficacy of ibafloxacin was tested in in vivo canine infection models. Ibafloxacin had good activity against Pasteurella spp., Escherichia coli, Klebsiella spp., Proteus spp. and Staphylococcus spp. (MIC90=0.5 µg/mL), moderate activity against Bordetella bronchiseptica, Enterobacter spp. and Enterococcus spp. (MIC50=4 µg/mL) and low activity against Pseudomonas spp. and Streptococcus spp. The time‐killing analysis confirmed that ibafloxacin was bactericidal with a broad spectrum of activity. The PAE and PA‐SME were between 0.7–2.13 and 1–11.5 h, respectively. Finally, studies in dog models of wound infection and cystitis confirmed the efficacy of once daily oral ibafloxacin at a dosage of 15 mg/kg. Additional studies are needed to better define the importance of AUC/MIC (AUIC) and Cmax/MIC ratios on the outcome of fluoroquinolone therapy in dogs.
Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection
Authors: Wong V. S. , Hughes V. , Trull A. , Wight D. G. D. , Petrik J. , Alexander G. J. M.
Published: March 2003

Patients with chronic hepatitis C virus (HCV) infection are often asymptomatic with few clinical signs of liver disease. Recognition of the presence of fibrosis or cirrhosis is difficult without liver biopsy, but with the availability of effective treatments, such as interferon, and the potential for progression to hepatoma in some cases, an accurate measure of the stage of disease is important. Serum hyaluronic acid (HA) has been identified as a potential marker of fibrosis or cirrhosis in other settings. In a prospective study in 130 chronic HCV carriers therefore, serum HA concentrations were compared with conventional liver function tests (including alanine aminotransferase (ALT), a‐glutathione‐S transferase (GST) and serum HCV RNA in order to determine which identified the stage of liver fibrosis as assessed by liver biopsy most accurately. The median HA concentrations according to the stage of fibrosis 0, 1&2, 3 and 4&5 were 17gl–1 (range 5– 37), 17gl–1 (5–80), 30gl–1 (10–105) and 350gl–1 (20–800) respectively. The median HA concentration in stage 4&5 was significantly greater than in stages 0, 1&2 or 3. Serum HA concentration rose with age, but even when adjusted for age the median HA at stage 4&5 was greater than all other groups (95% CI of difference between the medians exceeded 0). Thus, serum HA gave a sensitivity and specificity for stage 4&5 fibrosis of 85% and 88% respectively, exceeding those for ALT or GST. In contrast, serum ALT or GST levels were not correlated with the stage of fibrosis although ALT was significantly greater in the cirrhotic group when compared to the group with no fibrosis (stage 0). There was no correlation between serum HA and either the grade of inflammatory changes or serum HCV RNA. These results suggest that serum hyaluronic acid is a useful marker of liver fibrosis in patients with chronic HCV infection. It could therefore be used to monitor patients at risk of progressive fibrosis, in controlled clinical trials, as a measure of response to antifibrotic therapy and in those in whom liver biopsy is difficult or contraindicated.
Prediction of cirrhosis in patients with chronic hepatitis C infection by artificial neural network analysis of virus and clinical factors
Authors: Haydon G. H. , Jalan R. , Ala‐Korpela M. , Hiltunen Y. , Hanley J. , Jarvis L. M. , Ludlum C. A. , Hayes P. C.
Published: March 2003

The diagnosis of cirrhosis in patients with hepatitis C virus (HCV) infection is currently made using a liver biopsy. In this study we have trained and validated artificial neural networks (ANN) with routine clinical host and viral parameters to predict the presence or absence of cirrhosis in patients with chronic HCV infection and assessed and interpreted the role of the different inputs on the ANN classification. Fifteen routine clinical and virological factors were collated from 112 patients who were HCV RNA positive by reverse transcriptase–polymerase chain reaction (RT–PCR). Standard and Ward‐type feed‐forward fully‐connected ANN analyses were carried out both by training the networks with data from 82 patients and subsequently testing with data from 30 patients plus performing leave‐one‐out tests for the whole patient data set. The ANN results were also compared with those from multiple logistic regression. The performance of both ANN methods was superior compared with the logistic regression. The best performance was obtained with the Ward‐type ANNs resulting in a sensitivity of 92% and a specificity of 98.9% together with a predictive value of a positive test of 95% and a predictive value of a negative test of 97% in the leave‐one‐out test. Hence, further validation of the ANN analysis is likely to provide a non‐invasive test for diagnosing cirrhosis in HCV‐infected patients.
Analysis of hepatitis G virus infection markers in blood donors and patients with hepatitis
Authors: Brojer E. , Grabarczyk P. , Kryczka W. , Kucharski W. , Kubicka J. , Z·upánska B.
Published: March 2003

The incidence and clinical significance of hepatitis G virus (HGV) is still not fully known. The aim of our study was to assess the frequency of HGV RNA and antibody to HGV E2 protein (anti‐E2) in Polish blood donors and patients with hepatitis, and to compare the sequence of HGV clones with those reported by others. Two‐hundred and nineteen blood donors and 83 patients with hepatitis were studied. HGV was detected in 3.2% and anti‐E2 in 24.2% of blood donors and in 26.5% and 8.4% of patients with hepatitis, respectively. HGV was detected as a co‐infection with HCV in four of 18 patients with chronic hepatitis, in four of 16 patients with acute hepatitis and in one of six patients with fulminant liver failure (FLF), and as a co‐infection with HBV in one of six patients with FLF and in three of 10 patients with chronic hepatitis. In non‐A–C hepatitis, eight of 23 patients with acute hepatitis and one of four patients with FLF were positive for HGV but all 10 patients with chronic cryptogenic hepatitis were negative. In the follow‐up studies of patients with HGV alone, a correlation with viraemia and clinical symptoms was observed in two patients, but in three others HGV RNA was detected in spite of clinical resolution. Two HGV clones were sequenced, and the sequence of the HGV helicase region of the HGV isolates from donor and patient were homologous to those described by others. Hence, the frequency of HGV RNA in blood donors is similar to that obtained in other countries but the anti‐E2 (marker of a past infection) frequency is higher. The incidence of HGV RNA and anti‐E2 in hepatitis patients suggests that HGV plays a role in liver pathology, but careful analysis of individual cases does not confirm this.
Thymosin α1 treatment of chronic hepatitis B: results of a phase III multicentre, randomized, double‐blind and placebo‐controlled study
Authors: Mutchnick M. G. , Lindsay K. L. , Schiff E. R. , Cummings G. D. , Appelman H. D. , Peleman R. R. , Silva M. , Roach K. C. , Simmons F. , Milstein S. , Gordon S. C. , Ehrinpreis M. N.
Published: March 2003

Previous clinical trials have suggested that thymosin α1 (Tα1), an immunomodulatory peptide, may be effective in the treatment of chronic hepatitis B (CHB). The aim of this study was to determine the efficacy of Tα1 in a multicentre, placebo‐controlled and double‐blind study of 97 patients with serum hepatitis B virus (HBV) DNA‐ and hepatitis B e antigen (HBeAg)‐positive CHB. Patients who had been hepatitis B surface antigen (HBsAg) positive for at least 12 months entered a 3‐month screening period prior to randomization. Forty‐nine patients received Tα1 (1.6 mg) and 48 patients received placebo, twice weekly for 6 months, and were followed‐up for an additional 6 months. At inclusion, both groups were comparable for age, gender, histological grading, and aminotransferase and HBV DNA levels. A complete response to treatment, defined as a sustained serum HBV DNA‐negative status (two negative results at least 3 months apart) during the 12‐month study, with negative HBV DNA and HBeAg values at month 12, was seen in seven (14%) patients given Tα1 and in two (4%) patients treated with placebo (P = 0.084). Five (10%) patients given Tα1 and four (8%) patients given placebo exhibited a delayed response (defined as sustained serum HBV DNA negativity achieved after the 12‐month study period with negative HBV DNA and HBeAg values at the last assessment). A total of 12 (25%) patients given Tα1 and six (13%) patients given placebo showed a sustained loss of HBV DNA with a negative HBeAg value during or following the 12‐month study period (P < 0.11). These results do not confirm observations of treatment efficacy reported in other clinical studies.
Hepatitis C virus genotypes in France: relationship with epidemiology, pathogenicity and response to interferon therapy
Authors: Martinot‐Peignoux M. , Roudot‐Thoraval F. , Mendel I. , Coste J. , Izopet J. , Duverlie G. , Payan C. , Pawlotsky J. M. , Defer C. , Bogard M. , Gerolami V. , Halfon P. , Buisson Y. , Fouqueray B. , Loiseau P. , Lamoril J. , Lefrere J. J. , Marcellin P. ,   the GEMHEP
Published: March 2003

The aim of this study was to investigate the following in a large population of French patients with chronic hepatitis C: the geographical distribution of hepatitis C virus (HCV) genotypes; the relationship between HCV genotypes and epidemiological characteristics; severity of the disease; and response to interferon (IFN) therapy. Data from 14 tertiary referral centres, corresponding to 1872 patients with chronic hepatitis C, were prospectively collected from 1989 to 1997. HCV genotyping was performed using the line probe assay (LiPA). HCV genotypes 1b, 3, 1a, 2, 4 and a mixed infection were found in 41%, 22%, 16%, 11%, 4% and 4% of our population, respectively. HCV genotype distribution was homogeneous, except for genotype 2 that was found more frequently in the southwest than in the other regions (21%vs 9.2%) (P=0.001). HCV distribution was associated with gender, age, and source and duration of infection. In multivariate analysis, these correlations were related to the source of infection, which was the only independent factor significantly associated with genotype (P=0.001). Genotype 1b was significantly more common in patients with cirrhosis, but in multivariate analysis cirrhosis was independently related to older age at exposure and longer duration of infection (P=0.001). A sustained response to IFN therapy was observed in 11% of patients infected with genotypes 1a or 1b vs 32% of those infected with genotypes 2 or 3 (P=0.001). This study shows that HCV genotype is mainly related to the source infection, but not to the intrinsic pathogenicity of HCV, and is a strong predictor of sustained response to therapy.
Hepatitis A in patients with chronic liver disease – severity of illness and prevention with vaccination
Authors: Keeffe E.
Published: March 2003

Acute hepatitis A in patients with pre‐existing chronic liver disease (CLD) may theoretically predispose such patients to a more severe outcome of infection. The results of reports covering epidemics and case series suggest but do not universally support this possibility. An analysis of the larger case series support the suggestion that acute hepatitis A superimposed on chronic hepatitis B infection is associated with higher peak laboratory abnormalities, more severe disease and a higher fatality rate. The safety and immunogenicity of an inactivated hepatitis A vaccination was evaluated in patients with CLD and found to be satisfactory for the protection of this group of patients.
Prevalence and risk factors for the presence of serum cryoglobulins in patients with chronic hepatitis C
Authors: Cicardi  , Cesana  , Del Ninno  , Pappalardo  , Silini  , Agostoni  , Colombo
Published: March 2003

To assess the prevalence and risk factors for cryoglobulinaemia associated with hepatitis C virus (HCV) infection, we studied 360 consecutive patients with chronic hepatitis C (191 men, median age 57 years; 86 [24%] with cirrhosis). One‐hundred and sixty‐eight (47%) had circulating cryoglobulins (mean levels 208 ± 256 mg l−1), predominantly of type III (80%; and 20% type II). Cryoglobulins were more common in women than in men (56% vs 39%, P=0.001) and in patients with cirrhosis than in those with chronic hepatitis (57% vs 43%, P=0.024). Cryoglobulinaemic patients more frequently had high levels of serum immunoglobulin M (IgM) (57% vs 30%, P=0.001), immunoglobulin G (IgG) (84% vs 70%, P=0.002) and rheumatoid factor (45% vs 16%, P=0.001); low levels of serum C3 (15% vs 4%, P=0.001) and C4 (51% vs 26%, P=0.001); and low numbers of platelets (21% vs 12%, P=0.018), than patients without cryoglobulins. The presence of cryoglobulins was not correlated with hepatitis duration (cryopositives, 12 ± 7 years; cryonegatives, 11 ± 8 years) or HCV genotype (HCV 1b, 48% vs 53%; HCV 2a, 35% vs 29%, cryopositive vs cryonegative patients respectively). By multivariate analysis, female gender (odds ratio [OR] 1.675; confidence interval [CI] 1.055–2.661), elevated serum IgM (OR 2.296; CI 1.438–3.665), IgG (OR 1.952; CI 1.114–3.422), rheumatoid factor (OR 3.213; CI 1.889–5.465) and low C4 (OR 1.859; CI 1.138–3.038) could reliably predict the presence of cryoglobulins. When the pathogenic variables IgG, rheumatoid factor and C4 were excluded from analyses, only levels of serum cholinesterase activity < 4500 U independently predicted (OR 3.663, CI 1.258–10.184) the presence of cryoglobulins. Fifty per cent of the patients with chronic hepatitis C circulated cryoglobulins, with preference for those with a greater impairment of liver function, as revealed by serum cholinesterase activity.
Treatment of chronic hepatitis C genotype IV with interferon–ribavirin combination in Saudi Arabia: a multicentre study
Authors: Al‐Faleh  , Aljumah  , Rezeig  ,   Al‐Kanawi, Al‐Otaibi  , Alahdal  , Al‐Humayed  , Mayet  , Al‐Juhani  , Al‐Karawi  , George  , Sbeih
Published: March 2003

Between 1996 and 1997, we conducted a multicentre study to assess the effect of combination therapy of interferon (IFN) + ribavirin on chronic hepatitis C genotype 4. Ninety‐seven patients were enrolled. Sixty‐eight patients (47 male and 21 female) were non‐responders to previous therapy with IFN (Group I). Twenty‐nine patients (19 male and 10 female) were new (Group II). Following treatment with IFN, 23% in Group I and 9% in Group II had a sustained biochemical response. Only 12% in Group I and 5% in Group II achieved a sustained virological response. Virus load was found to be the major factor determining response, followed by histology grading and staging. Like HCV genotype 1, HCV genotype 4 seems to have a poor response to therapy.
Biochemical and structural analysis of the NS5B RNA‐dependent RNA polymerase of the hepatitis C virus
Authors: Lohmann  , Roos  , Körner  , Koch  , Bartenschlager
Published: March 2003

Hepatitis C virus (HCV), the major causative agent of chronic and sporadic non‐A, non‐B hepatitis worldwide, is a distinct member of the Flaviviridae virus family. These viruses have in common a plus‐strand RNA genome that is replicated in the cytoplasm of the infected cell via minus‐strand RNA intermediates. Owing to the lack of reliable cell culture systems and convenient animal models for HCV, the mechanisms governing RNA replication are not known. As a first step towards the development of appropriate in vitro systems, we expressed the NS5B RNA‐dependent RNA polymerase (RdRp) in insect cells, purified the protein to near homogeneity and studied its biochemical properties. It is a primer‐ and RNA template‐dependent RNA polymerase able to copy long heteropolymeric templates without additional viral or cellular cofactors. We determined the optimal reaction parameters, the kinetic constants and the substrate specificity of the enzyme, which turned out to be similar to those described for the 3D polymerase of poliovirus. By analysing a series of nucleosidic and non‐nucleosidic compounds for their effect on RdRp activity, we found that ribavirin triphosphates have no inhibitory effect, providing direct experimental proof that the therapeutic effect observed in patients is not related to a direct inhibition of the viral polymerase. Finally, mutation analysis was performed to map the minimal NS5B sequence required for enzymatic activity and to identify the ‘classical’ polymerase motifs important for template and NTP binding and catalysis.
Hepatitis C is more severe in drug users with human immunodeficiency virus infection
Authors: Romeo  , Rumi  , Donato  , Cargnel  , Viganò  , Mondelli  , Cesana  , Colombo
Published: March 2003

Drug users with chronic hepatitis C virus (HCV) infection are frequently co‐infected with human immunodeficiency virus‐1 (HIV‐1), but it is still not clear whether HIV‐1 worsens the natural history of hepatitis C. To investigate this, we conducted a multicentre observational study in 163 drug addicts with histologically documented hepatitis C, 92 of whom were also infected with HIV‐1: 25 (27%) were CDC stage II, 53 (58%) were CDC stage III and 14 (15%) were CDC stage IV. Eighty‐eight (54%) patients had chronic hepatitis (CH) with minimal activity, 28 (17%) had CH with moderate activity, 40 (25%) had CH with severe activity and seven (4%) had active cirrhosis. Twenty‐one HIV‐negative patients and 15 HIV‐positive patients admitted to alcohol abuse (29% vs 16%, P=0.0665). Liver disease was more severe in HIV‐positive patients than in HIV‐negative ones (P=0.0198): 34 HIV‐positive patients and 13 HIV negatives had severe CH and cirrhosis. These two severe liver diseases were seen more often in HIV‐positive patients with a history of alcohol abuse than in HIV‐negative patients (10 out of 16 vs seven out of 21). Age, alcohol abuse and distribution of the histological categories of liver disease were statistically different in HIV‐infected and HIV‐uninfected patients. Multivariate analysis showed that age, alcohol abuse and serum antibodies to HIV were independently associated with severe CH or cirrhosis. Thus, HIV may enhance the risk of severe liver disease in drug users with hepatitis C, independently of the degree of immune dysfunction. Alcohol abuse may contribute independently, aggravating the cause of HCV‐dependent liver disease.
Sustained response to interferon‐α2a monotherapy of young blood donors with minimal‐to‐mild chronic hepatitis C
Authors: Prati  , Zanella  , Zanuso  , Vianello  , Torre E. Della , Mozzi  , Carriero  , Zahm  , Donato  , Colombo  , Sirchia  ,   for the Donor Surveillance Study Group
Published: March 2003

Subjects with minimal‐to‐mild chronic hepatitis C may suffer long‐term consequences of hepatitis C virus (HCV) infection. Nonetheless, they are not candidates for antiviral treatment, mainly because little data are available concerning the efficacy and safety of therapy. Thirty‐two HCV RNA positive individuals aged 18–45 years, who had a histological activity index score ≤ 8 and alanine aminotransferase (ALT) levels ≤ 1.5 times lower than the normal limit for at least 1 year, were prospectively enrolled among a cohort of 35358 candidate blood donors, and treated with 4.5 mega units (MU) of recombinant interferon‐α2a (IFN‐α2a) thrice weekly for 6 months, and for an additional 6 months if a virological response was observed. Twelve months after the completion of treatment, 13 of 31 evaluable patients were HCV RNA negative, accounting for a sustained response rate of 42%. Patients without fibrosis had a lower response rate than those with mild fibrosis (two of 14 vs 11 of 17; P=0.012). In responders, median aminotransferase levels were significantly lower after therapy than before (11.04 ± 3.98 vs 27.3 ± 12.32 U l−1, respectively; P < 0.005). When the analysis was limited to the six responders whose pretreatment aminotransferase levels were consistently normal, this difference was still significant (9.33 ± 4.12 vs 20.58 ± 6.73 U l−1; P=0.002). In conclusion, a durable suppression of viraemia can be obtained by IFN monotherapy in a relatively high proportion of young subjects with minimal‐to‐mild chronic hepatitis C, especially when portal fibrosis is found on liver biopsy. The disappearance of viraemia always leads to a reduction in the degree of hepatocellular necrosis.
In vitro effect of thymosin‐α1 and interferon‐α on Th1 and Th2 cytokine synthesis in patients with chronic hepatitis C
Authors: Andreone P. , Cursaro C. , Gramenzi A. , Margotti M. , Ferri E. , Talarico S. , Biselli M. , Felline F. , Tuthill C. , Martins E. , Gasbarrini G. , Bernardi M.
Published: March 2003

Current evidence suggests that increased expression of Th1‐associated cytokines is important for immune‐mediated eradication of hepatitis C infection, while an increase in Th2‐associated cytokines is associated with persistence of infection. In this study we evaluated the effects of thymosin‐α1 (TA1), a naturally occurring thymic peptide, and interferon‐α (IFN‐α) on cytokine production in peripheral blood mononuclear cells from untreated patients with chronic hepatitis C. We examined the effect of incubation with TA1, IFN‐α, or both, on production of Th1‐associated cytokines (IL‐2, IFN‐γ), Th2‐associated cytokines (IL‐4, IL‐10), and synthesis of the antiviral protein 2′,5′‐oligoadenylate synthetase. TA1 treatment induced a significant increase in production of IL‐2 and 2′,5′‐oligoadenylate synthetase. Smaller increases were also seen after treatment with IFN‐α, while incubation with TA1 and IFN‐α together led to an additive or synergistic effect. Incubation with TA1 resulted in a decrease in IL‐4 and IL‐10, whereas IFN‐α increased these cytokines. The addition of TA1 to IFN‐α significantly reversed this IFN‐α‐induced increase. Hence, TA1 treatment could benefit patients with hepatitis C infection by increasing the Th1‐type response, fundamental for sustained clearance of hepatitis C; and by decreasing the Th2‐type response, associated with persistence of viraemia.
TT virus infection in Italy: prevalence and genotypes in healthy subjects, viral liver diseases and asymptomatic infections by parenterally transmitted viruses
Authors: Masia G. , Ingianni A. , Demelia L. , Faa G. , Manconi P. E. , Pilleri G. , Ciancio A. , Rizzetto M. , Coppola R. C.
Published: March 2003

This study was aimed to evaluate TT virus prevalence in subjects with hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections in patients affected by hepatitis of unknown origin (non‐A–non‐E hepatitis) and in healthy subjects who had not been exposed to HBV, HCV and HIV. A total of 317 subjects were tested; 40 were HBsAg asymptomatic carriers, 57 subjects were anti‐HCV positive (45 without chronic hepatitis and 12 with HCV‐related chronic hepatitis), and 27 had chronic non‐A–non‐E hepatitis. Fifty‐seven subjects were intravenous drug users (IVDUs) (52 with HCV or/and HIV infections), seven patients underwent a liver transplant for fulminant hepatitis and 137 were healthy subjects from the general population. Overall, TTV‐DNA was detected in 62 subjects (19.6%): in 17.9% of the HBsAg carriers, in 14% of the anti‐HCV‐positive patients (in 8.3% and in 15.5% of patients with and without chronic hepatitis, respectively), in 22.2% of non‐A–non‐E hepatitis patients, in 22.8% of IVDUs, in 57.1% of fulminant hepatitis patients. TTV‐DNA was also found in 20.4% healthy subjects. The prevalence in the different subgroups was not statistically different. The genotypes were identified in 40 of the 62 (64.5%) TTV‐DNA positive samples: genotype 1a in 17.5%, 1b in 27.5%, genotype 2 in 27.5%, genotype 3 in 15.0%, genotype 4 in 5.0% and genotype 5 in 7.5%; the genotype distribution in the subsets of patients was not significantly different. In conclusion, this study showed that TTV infection is common in Italy; it is widespread throughout the entire population and five genotypes are present in Sardinia. Our results further dismiss the role of TTV as cofactor in influencing the clinical course of infections with other hepatitis viruses as well as the role of HIV in enhancing TTV transmission and replication.
Constrained genomic and conformational variability of the hypervariable region 1 of hepatitis C virus in chronically infected patients
Authors: Hino K. , Korenaga M. , Orito E. , Katoh Y. , Yamaguchi Y. , Ren F. , Kitase A. , Satoh Y. , Fujiwara D. , Okita K.
Published: March 2003

We analysed the genomic and conformational variability of the hypervariable region 1 (HVR1) of the hepatitis C virus (HCV) to evaluate the importance of its biological role. A total of 865 genotype 1b HVR1 subclones were collected from serially sampled sera in 11 patients with chronic hepatitis C, four of whom received interferon therapy. Consequently, 169 distinct sequences were examined for amino acid substitutions as well as hydrophilic or hydrophobic profile at each amino acid position within HVR1. Secondary structure of HVR1 was also predicted by the method of Robson in 90 distinct sequences from eight patients, including three interferon‐treated patients. Some positions within the HVR1 were invariable or nearly so as to amino acid substitution. Hydrophilic or hydrophobic residues exclusively predominated at several positions. These constrained amino acid replacement and hydrophilic or hydrophobic profiles were conserved irrespective of interferon therapy, though the frequency of amino acid replacement was greater at almost all amino acid positions within the HVR1 in interferon‐treated patients. The quasispecies of HCV showed various secondary structures of HVR1, but many sequences seemed to have common characteristics. β sheet conformations around both the N‐terminus and position 20 (numbered from the NH2 terminus of E2 envelope glycoprotein), and/or coil structures around the C‐terminus of HVR1 could be identified. These results suggest that HVR1 amino acid replacements are strongly constrained by a well‐ordered structure, in spite of being tolerant to amino acid substitutions, and imply an important biological role of the HVR1 protein in HCV replication.
Autocorrelated data in telemetry studies: time to independence and the problem of behavioural effects
Authors: Rooney S. M. , Wolfe A. , Hayden T. J.
Published: March 2003

Independence of locational fixes, to reduce the effects of autocorrelation, is often deemed a prerequisite for estimation of home range size and utilization when using data derived from telemetric studies. Three methods of estimating times to independence using movement estimates, along with a statistical method of estimating the level of autocorrelation of locational data, were examined for two species of mammal. Attempts to achieve statistically independent data by subsampling resulted in severe redundancy in the data and significant underestimation of range size and rates of movement. Even a sample interval of one fix per week did not guarantee independence and also resulted in underestimation of range size despite range asymptotes being reached. It would appear that the correct strategy for the best possible estimation of range size and use from telemetry would be the repeated use of as short a sampling interval as is possible over an extended period of time. Statistical methods to measure levels of autocorrelation in locational data may be useful for comparing rates of range use between different populations of the same species or between species, as long as the same sample interval is used.
The origins and character of ‘aboriginal subsistence’ whaling: a global review
Authors: REEVES RANDALL R.
Published: March 2003

The International Whaling Commission (IWC) recognizes aboriginal subsistence whaling to be distinct from commercial whaling, and these two broad categories of whaling are subject to different management approaches. This paper describes recent, ongoing and likely future whale hunts that qualify, or may qualify, for aboriginal subsistence status within the IWC’s management framework. To ensure conservation of the whale populations, a forthright exposition of the origins, development and character of these hunts is needed in addition to stock assessment, a risk‐averse catch limit algorithm and appropriate mechanisms within the whaling communities to ensure compliance. The hunts for Bowhead Whales (Balaena mysticetus) and Gray Whales (Eschrichtius robustus) in the Arctic and North Pacific, respectively, and Sperm Whales (Physeter macrocephalus) in Indonesia have long histories and local origins. Those for Humpback Whales (Megaptera novaeangliae) in the Lesser Antilles and at Tonga in the South Pacific were introduced by foreign commercial whalers. Whale hunting in the Philippines appears to have originated both locally and as a result of foreign influence. The relatively recent initiation of whaling for Fin Whales (Balaenoptera physalus) and Minke Whales (Balaenoptera acutorostrata) in Greenland required introduced technology but can be viewed as a modern adaptation of an ancient tradition. Consensus in deciding how to classify and manage non‐industrial whaling has been, and will remain, elusive. Even with common definitions of key terms such as ‘subsistence’, ‘commercial’ and ‘aboriginal’, interpretations will depend on whether one’s priorities are whale‐centred or human‐centred.
Efficacy of tags impregnated with pheromone and acaricide for control of Amblyomma variegatum
Authors: ALLAN SANDRA A. , BARRÉ NICOLAS , SONENSHINE DANIEL E. , BURRIDGE MICHAEL J.
Published: March 2003

The efficacy of tags impregnated with pheromone and acaricide for control of Amblyomma variegatum on cattle in Guadeloupe was determined for a 13‐week trial. Comparisons were made between untreated cattle and cattle with tags containing either pheromones alone (o‐nitrophenol, methyl salicylate, 2,6‐dichlorophenol and phenylacetaldehyde), pheromones plus acaricide (cyfluthrin or deltamethrin), or acaricide alone. Tags were fastened to cattle both on collars on the neck and with adhesive to tail hairs, with over 98 and 90% of tags retained, respectively, during the trial. By the end of the trial, tick infestations increased on untreated cattle (311.7%) and cattle with pheromone tags (154.8%) but decreased on cattle with pheromone/cyfluthrin (–45.0%), cyfluthrin (–42.8%), pheromone/deltamethrin (–68.7%) and deltamethrin tags (–87.6%). Cattle with pheromone tags had greater proportions of ticks on the hind regions (81%) compared to untreated cattle (62.5%) and on the front regions (18.2%) compared to untreated cattle (8.2%) indicating that ticks aggregated in response to pheromones. Analysis of hair samples by gas chromatography indicated that, within 2 days of placement, cyfluthrin spread rapidly over the body from the tags. Both cyfluthrin and deltamethrin were present in detectable levels on all eight body regions examined throughout the trial. Analysis of the tags indicated that they all still contained pheromone components after 13 weeks under field conditions.
Dissemination barriers to Ross River virus in Aedes vigilax and the effects of larval nutrition on their expression
Authors: Jennings C. D. , Kay B. H.
Published: March 2003

Effects of larval nutrition on vector competence of the mosquito Aedes vigilax (Skuse) (Diptera: Culicidae) from Townsville, north Queensland, for Ross River virus (RR) were examined. Larvae were reared on three different diets to create three significantly different size classes of adult mosquito. These were fed on serial dilutions of RR and then sampled on alternate days so the progression of the virus through the mosquito could be examined. No differences of vector competence could be attributed to larval nutrition. Barriers to infection and the correlation between infection rate, viral titre and transmission of RR by Ae. vigilax were also examined. The mesenteronal barrier was the only infection barrier expressed. No correlation between viral titre and transmission was detected, but a strong correlation was found between salivary gland infection and transmission rate. From this it was possible to estimate that 98.7 ± 1.3% of Ae. vigilax with infected salivary glands transmit RR.
Biochemical characterization of insecticide resistance in the German cockroach, Blattella germanica, from Malaysia
Authors: Lee C. Y. , Hemingway J. , Yap H. H. , Chong N. L.
Published: March 2003

The possible insecticide resistance mechanisms of four Malaysian field‐collected strains of the German cockroach,Blattella germanica(Linnaeus) (Dictyoptera: Blattellidae), were characterized with biochemical assays and native polyacrylamide gel electrophoresis (PAGE). Elevated esterase activity (at low to moderate frequency) and altered acetylcholinesterase (low frequency) were detected in all field strains, while elevated glutathione S‐transferase levels were present in only two strains. Seven esterase bands were separated by native PAGE; a greater intensity occurred in three bands in the resistant strains compared to the susceptible strain. Inhibition studies using specific inhibitors on polyacrylamide gels suggested that the slowest of these three esterases is a cholinesterase, while the other two are carboxylesterases with a preference for β‐ over α‐naphthyl acetate.
Human sweat and 2‐oxopentanoic acid elicit a landing response from Anopheles gambiae
Authors: Healy T. P. , Copland M. J. W.
Published: March 2003

A wind tunnel bioassay and video to observe mosquitoes landing on heated glass cylinders were used to test sweat and some derivatives for responses of Anopheles gambiae Giles (Diptera: Culicidae), a highly anthropophilic African species of malaria vector. Filter papers impregnated with human sweat and a diethyl ether extract from the filter papers elicited significantly more landings than a water control (P < 0.001). The concentration of lactic acid in the extract was determined by GLC assay, but bioassays of an equivalent dose of lactic acid (from a commercial supplier) did not elicit landings. Chemical analysis of the extract by combined GLC/mass spectrometry indicated the presence of 73 compounds, of which 40 were tentatively identified. The major components of the extract were aliphatic carboxylic acids. An artificial blend of 22 carboxylic acids did not elicit landings. Bioassays of 2‐oxopentanoic acid elicited significantly more landings (P < 0.001). The possible importance of oxo‐carboxylic acids for host‐seeking by anthropophilic mosquitoes is discussed and their use for trapping is suggested.
Control of flea populations in a simulated home environment model using lufenuron, imidacloprid or fipronil
Authors: Jacobs D. E. , Hutchinson M. J. , Ryan W. G.
Published: March 2003

Control strategies were evaluated over a 6‐month period in a home simulation model comprising a series of similar carpeted pens, housing matched groups of six cats, in which the life‐cycle of the fleaCtenocephalides felis felisBouché (Siphonaptera: Pulicidae) had been established. Additional adult fleas were placed on the cats at intervals to mimic acquisition of extraneous fleas from outside the home. Treatment strategies included a single subcutaneous deposition of injectable lufenuron supported by initial treatments with a short‐acting insecticidal spray, or monthly topical applications of imidacloprid or fipronil. An untreated control group indicated that conditions were suitable for flea replication and development. Controls had to be combed on 18 occasions to remove excessive flea burdens and two developed allergic reactions. Lufenuron cats were combed once and required two insecticidal treatments in the first month to achieve control. Even so, small flea burdens were constantly present thereafter. Imidacloprid and fipronil treatments appeared to give virtually complete control throughout. Single fleas were found on imidacloprid cats on two occasions, whereas none were recovered from fipronil cats at any time after the first treatment. Tracer cats were used to monitor re‐infestation rates at the end of the trial period. Small numbers of host‐seeking fleas were demonstrated in all treatment pens, indicating that total eradication had not been accomplished. It is concluded that the home environment simulation model incorporating tracer animals could provide a powerful tool for studying flea population dynamics under controlled conditions but improved techniques are needed for quantifying other off‐host life‐cycle stages.
Phlebotomine sandfly responses to carbon dioxide and human odour in the field
Authors: Pinto M. C. , Campbell‐Lendrum D. H. , Lozovei A. L. , Teodoro U. , Davies C. R.
Published: March 2003

Abstract.Responses ofLutzomyiasandflies (Diptera: Psychodidae: Phlebo tominae) to carbon dioxide (CO2) and human odour were investigated by field experiments in Paraná State, southern Brazil. Catches of two predominant species:Lu. intermedia(Antunes & Coutinho) andLu. whitmaniLutz & Neiva, were compared between traps baited with a human adult or with CO2emitted at the human‐equivalent rate. When the baits were only 40 cm apart, no difference of attractiveness was detected. When baits were separated by 20 m, however, significantly fewer sandflies (44%Lu. intermedia, 46%Lu. whitmani) were trapped with CO2compared with human bait. This is the first field evidence that anthropophilic sandflies are attracted by human kairomones in addition to CO2.For both species, the proportion of human attractiveness attributable to CO2was significantly less for males than females; forLu. intermediamales human bait was no more attractive than CO2alone. Gender differences in sandfly olfactory sensitivity are likely to be associated with behavioural differences on the host, where females feed on blood and males find mates. With traps 20 m apart, bothLutzomyiaspp. showed roughly linear increased responses (log–log scale) to 0.08–0.55% CO2equivalent to 0.5–4 humans. This would explain why host size is generally proportional to attractiveness, as observed for other species of phlebotomine sandflies.
Toxicity and behavioural effects of diet‐borne alkaloids on larvae of the black blowfly, Phormia regina
Authors: Green P. W. C. , Simmonds M. S. J. , Blaney W. M.
Published: March 2003

Abstract Larvae of the black blowfly, Phormia regina (Meigen) (Diptera: Calliphoridae) were exposed for 24 h to artificial diets that contained one of the following alkaloids: arecoline, caffeine, nicotine, quinine, sparteine or strychnine at either 1000 or 100 p.p.m. Each of the alkaloids caused reduced weight gain, relative to a control population in a no‐choice bioassay and, with the exception of quinine, all alkaloids caused reduced larval weights in a choice bioassay. Larvae were unable to move away from diets containing arecoline (1000 and 100 p.p.m) and congregated away from diets containing 1000 p.p.m. quinine. Arecoline (1000 p.p.m) and both concentrations of nicotine caused significant mortality of larvae. Over a longer period (120 h), 10 and 1 p.p.m. nicotine resulted in significant numbers of larvae congregating away from a treated diet. Ten p.p.m. nicotine caused reduced weight gain over 120 h, although larvae provided with a choice were less affected. Exposure of larvae to dried residues of nicotine for 2 h did not affect subsequent development.
Development and integration of CAL: a case study in medicine
Authors: Hamilton  , Furnace  , Duguid  , Helms  , Simpson
Published: March 2003

Context

The Faculty of Medicine and Medical Sciences at the University of Aberdeen viewed the use of Computer Assisted Leaning (CAL) and other IT based learning resources as a possible way of coping with an increase in student numbers whilst maintaining or increasing the quality of medical teaching.

Objectives

Our primary objective was to develop and integrate Computer Assisted Learning (CAL) applications into the undergraduate medical curriculum.

Subjects/Materials

A wide spectrum of CAL applications were developed dealing with many topics in the curriculum.

Methods

We formulated a structured approach to CAL development by establishing a team of professionals (forming a CAL Unit), using existing expertise and by implementing a process to ensure that the CAL had a maximum impact upon the curriculum. The CAL included multimedia tutorials, learning guides, computer aided assessment (CAA) and Model Patients.

Results

There are now over 150 IT based learning resources in our curriculum and course evaluation has showed that these have been well received by students.

Conclusions

We conclude that with the wise use of the many skills and facilities usually available within an institution and by promoting collaborative projects with others, the production of high quality CAL is possible within most institutions.
Approaches to experiential learning, course delivery and validation in medicine. A background document
Authors: Stanton Frances , Grant Janet
Published: March 2003

Educational models and approaches change over time in their dominance and use, offering a wide selection to educational planners and teachers. This paper discusses aspects of experiential learning, distance learning, learning contracts, portfolios, reflection, appraisal, assessment and validation of education. It offers triggers to further thought and enables the analysis of current educational practice.
A Delphi technique to identify and evaluate criteria for construction of PBL problems
Authors: Marchais Jacques E Des
Published: March 2003

Introduction

In the process of PBL implementation, faculty members often ask what are the criteria for constructing problems and subsequently evaluating them. Although experts agree on a fundamental theoretical basis for developing problems, mostly prototypical, it is difficult to find specific criteria that could be used in constructing PBL problems.

Method

A Delphi technique using six independent judges from the Rouen School of Medicine, France, answered this question. It took four rounds and five months.

Results

Nine criteria were identified and rank‐ordered according to their relative importance: 1 – stimulating thinking, analysis, and reasoning (openness 6·8 points); 2 – assuring self‐directed learning (autonomy 6·5); 3 – using previous basic knowledge (richness 6·2); 4 – proposing a realistic context (attractiveness 5·7); 5 – leading to the discovery of learning objectives (coverage 5·0); 6 –arousing curiosity (inquisitiveness 5·0); 7 – choosing topics related to public health (relevance 5·0); 8 – assuring contextual breadth (comprehensiveness 4·8); and 9 – choosing an appropriate vocabulary (medical encoding 4·7).

Discussion

The identification represents a fresh outlook on the PBL process, from judges who had recent experience in constructing PBL problems. Related to Barrow’s dimensions, these criteria could be seen as a more concrete and specific level of conceptualization. Paired with those found in the literature, they match six out nine already identified, although not prioritized criteria.

Conclusion

Judges from a school just having implemented PBL, found that Reasoning and Autonomy are the most important criteria for constructing PBL problems.
Molecular phylogeography and the evolution and conservation of Amazonian mammals
Authors: DA SILVA MARIA NAZARETH F. , PATTON JAMES L.
Published: March 2003

The phylogeographic structure of 15 genera of Amazonian marsupials and rodents is summarized based on comparative sequence of the mitochondrial cytochrome b gene. The data are limited in geographical coverage, with samples widely scattered throughout Amazonia from the base of the Andes in Peru to the Guianan coast and eastern Brazil. We use this approach to define species boundaries, based minimally on the principle of reciprocal monophyly, in conjunction with morphological or other genetic discontinuities. The taxa so defined are older than previously appreciated, with many lineages dating from 1 to more than 3 Myr, and thus apparently predating the early Pleistocene. We relate patterns of concordant geographical shifts with underlying tectonic history and to current positions of major rivers. Finally, we provide comments on the utility of these data and patterns to conservation, articulating a need to incorporate phylogeographic information as part of the rationale in establishing conservation priorities at the organismal and geographical area levels.
Island models and the coalescent process
Authors: HUDSON RICHARD R.
Published: March 2003

Using a coalescent approach, we derive several classical results and extend them to more general models. We find that the classic result for constant population size and constant migration rates holds in models with varying population size and varying migration rates with the obvious substitution of effective population size and mean migration fraction. In addition, the relationship of a ‘local’FSTto local gene flow is derived. This result may be useful for analysing gene flow in a regional subset of a large global population, using only data from the regional subset.