The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm.

The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing.

High-dose silibinin rescue treatment for HCV-infected patients showing suboptimal virologic response to standard combination therapy.

Incomplete suppression of hepatitis C virus (HCV) replication with persistence of minimal viremia (partial virologic response) leading to treatment failure can be observed in a significant proportion of HCV type 1-infected patients during antiviral therapy. Recently, high-dose intravenous silibinin has demonstrated strong antiviral activity against HCV. We were therefore interested in whether patients with partial virologic response can be rescued by the on-treatment addition of a short-term course of high-dose intravenous silibinin infusions. Twenty patients who failed to achieve a complete virologic response to different interferon-based regimens qualified for the rescue strategy and received 1400 mg/day silibinin infusions on two consecutive days. Complete viral suppression (below the limit of detection <6 IU/mL, TMA assay) could be induced in 13 of 20 patients within the first week after the short-term silibinin infusion, and all but one of them also remained HCV RNA negative during the subsequent follow-up period on continued peginterferon plus ribavirin treatment. In the remaining seven patients, no complete suppression could be achieved although four showed a significant HCV RNA reduction in response to silibinin. Silibinin infusions were generally well tolerated, and activation of abdominal peristalsis with nausea, diarrhoea and vomiting were the most prominent side effects. Of the twelve patients who exhibited a durable response to peginterferon and ribavirin treatment, three achieved an SVR, two achieved a week 12 SVR and four suffered a viral relapse. Three patients could not complete the assigned antiviral treatment with peginterferon alpha and ribavirin for nonvirological reasons. Short-term administration of high-dose intravenous silibinin might be an interesting approach to rescue patients with ongoing minimal residual viremia while on interferon-based therapy. These preliminary findings may stimulate further studies to evaluate more refined therapeutic strategies.

Effects of variety, cropping year, location and fertilizer application on nutritive value of durum wheat straw.

This study was carried out to assess the effects of variety, year, location and level of fertilizer application on chemical composition and in sacco dry matter (DM) degradability of durum wheat straw as well as to understand the relationship between straw quality and agronomic traits of the crop and to assess the possibilities of selecting wheat varieties that combine high grain yield with desirable straw quality. Two local (Arendeto and Tikur sinde) and two improved (Boohai and Gerardo) varieties of durum wheat (Triticum turgidum Desf.) were used in the experiment. The four varieties were grown at two locations (Akaki and Ejere) in the years 2001/2002 and 2002/2003 in 5 x 5 m plots in three replications. Diammonium phosphate and urea fertilizers were applied at four levels (0/0, 32/23, 41/23 and 64/46 kg/ha of nitrogen/phosphorus). Straw quality was assessed based on chemical composition and in sacco DM degradability. Correlation of straw quality with grain and straw yield and with other agronomic characteristics of the crop was determined. The potential utility index (a measure that integrates grain and digestible straw yield) was used for ranking of the varieties. The local varieties had higher crude protein (CP) and lower neutral detergent fibre contents and higher digestibility than the improved varieties. The cropping year and location had significant effect on CP content and degradability of the straw, which could be due to climatic variation. However, the fertilizer level did not have any significant effect on straw quality except that the CP content of the straw tended to increase with increasing level of fertilizer application. Based on the potential utility index the varieties ranked, in a decreasing order, as Tikur sinde > Arendeto > Gerardo > Boohai and the ranking was consistent across years and locations. Except the CP content, straw quality was not negatively correlated with grain and straw yield. This indicates that there is a possibility of selecting varieties of wheat that combine high grain and straw yield with desirable straw quality.

Vitamin E supplementation does not mitigate the acute morbidity effects of porcine reproductive and respiratory syndrome virus in nursery pigs.

The objective of this study was to determine whether feeding a vitamin E-rich diet would benefit nursery pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). Sixty-four pigs were subjected to one of four treatment combinations (2 x 2 factorial) of dietary vitamin E (adequate or excess) and PRRSV (medium or inoculation with VR-2385 isolate P-129). Pigs were fed experimental diets during a 3-wk period before inoculation as well as during a 12-d period after inoculation. Growth performance was determined throughout the study, and lipid peroxidation in liver, glutathione peroxidase (GPX) activity in serum, circulating white blood cells, and serum interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) were determined in samples collected from pigs killed 4 or 12 d after inoculation. Infection by PRRSV (P < 0.001) induced a marked decrease in both ADFI and ADG, but neither the main effect of diet nor the diet x PRRSV interaction was significant. Neither diet nor PRRSV affected feed efficiency. At 12 d after inoculation, lipid peroxidation in liver and GPX activity in serum were lower in pigs fed excess vitamin E than in those fed adequate vitamin E (P < 0.01), suggesting that the diet high in vitamin E bolstered the antioxidant status of the pigs. However, PRRSV did not affect lipid peroxidation in liver or serum GPX activity, and the diet x PRRSV interaction was not significant. White blood cell counts were decreased and IFN-gamma, and IL-1beta were increased (P < 0.05) 4 and 12 d after inoculation in PRRSV-infected pigs, but neither diet nor the diet x PRRSV interaction was significant. Collectively, these results indicate that increasing antioxidant defenses by feeding high levels of vitamin E did not ameliorate the effects of PRRSV on decreased growth, leukopenia, and increased serum IL-1beta and IFN-gamma. Thus, feeding nursery pigs a diet high in vitamin E may not be useful for mitigating the acute morbidity effects of PRRSV infection.

Transscleral laser thermotherapy of hamster Greene melanoma: inducing tumour necrosis without scleral damage.

The feasibility of using transscleral thermotherapy (TSTT) to induce necrosis of choroidal melanoma without causing damage to the sclera was investigated. Fifty-two subcutaneously implanted hamster melanomas covered by human donor sclera were irradiated for 1 min with an 810 nm laser using a 3 mm spot diameter, with and without cooling of the scleral surface. Immediately after irradiation the temperature of the scleral surface was measured with an infrared camera. Irradiation at 2000 mW, without cooling of the sclera, resulted in tumour necrosis to a mean depth of 4.4 mm and a mean diameter of 5.5 mm, without causing damage to the scleral collagen; the surface temperature of the sclera was 44.5 degrees C, and the estimated temperature at the sclera-tumour interface was 60.1 degrees C. There was a sharp demarcation between the viable and the necrotic part of the tumour. TSTT at 2500 mW, without cooling of the sclera, caused maximal tumour necrosis to a mean depth of 5.2 mm and a mean diameter of 5.9 mm; the scleral layers adjacent to the tumour had an estimated temperature of 67.6 degrees C and showed signs of damage in 14% of the experiments. Cooling of the sclera resulted in less thermal damage to the sclera but also less tumour necrosis. Results indicate that TSTT has potential in the treatment of choroidal melanoma.

Temperature dependence of thermal damage to the sclera: exploring the heat tolerance of the sclera for transscleral thermotherapy.

Thermal damage to the human sclera in relation to temperature and duration of exposure was studied in order to determine the heat tolerance of the sclera with respect to transscleral thermotherapy of choroidal melanoma. Samples of human sclera were submerged in saline for 10 sec to 10 min at temperatures of 37-100 degrees C. The effects of heat on the shape, weight and size of the samples were studied. Thermal damage of scleral collagen was examined by polarized light microscopy (LM) and electron microscopy (EM). The sclera was embedded in epoxy resin and stained with toluidine blue for LM and with uranyl acetate and lead citrate for EM. Thermal damage of scleral collagen on polarized LM was graded on a five point scale. Scleral damage was visible on macroscopic examination and on LM and EM in sclera heated at 65 degrees C for 20 sec or longer, at 70 degrees C for 10 sec or longer, and at higher temperatures. A sigmoidal function was used to define the relation between temperature and changes in diameter, thickness, and weight of scleral samples. Using fitted functions, the threshold temperature for thermal damage was estimated to be 59-61 degrees C when samples were heated for 10 min, 62-63 degrees C when heated for 1 min, and 66-67 degrees C when heated for 10 sec; the threshold exposure time at 60 degrees C was estimated to be 7-12 min. These results indicate a temperature of 60 degrees C for 1 min is well tolerated by human donor sclera; information of in vivo studies is required to validate whether this setting can be used in transscleral thermotherapy (TSTT) for choroidal melanoma.

Identification of Melissa officinalis Subspecies by DNA Fingerprinting.

The random amplified polymorphic DNA analysis (RAPD) is a method to study genetic variability within and between populations and species on the basis of the amplification of anonymous fragments from genomic DNA templates by means of polymerase chain reaction (PCR). We applied RAPD analysis in order to distinguish medicinal plant subspecies at the level of their genomes. In this study we investigated various samples of two MELISSA subspecies and showed that RAPD analysis is a fast and reliable method to distinguish subspecies on the pharmaceutical market that have been previously classified according to the distribution pattern of compounds present in the lemon balm oil.

Epidemiological and clinical aspects of hepatitis G virus infection in blood donors and immunocompromised recipients of HGV-contaminated blood.

BACKGROUND AND OBJECTIVES: The infectiousness and clinical relevance of the newly discovered blood-borne Flaviviridae-like agent, termed hepatitis G virus (HGV), are not well understood. MATERIALS AND METHODS: Twenty-three transfusion recipients of two HGV-affected long-term blood donors were studied for HGV genome and antibodies to the putative envelope 2 glycoprotein (anti-E2) of HGV. Nine recipients had nonhematological disorders and 14 suffered from severe hematological diseases and 7 of them received allogeneic bone marrow or blood stem cell transplantation. The molecular epidemiology of the observed HGV infection was studied by direct sequencing of parts of the 5'-noncoding region, NS3, and NS5 region of HGV in the 2 long-term donors and in their 6 recipients who became HGV RNA positive. Additionally, 549 individuals-homologous (n = 254) and autologous blood donors (n = 202), and medical staff (n = 89)--were investigated for the presence of HGV RNA. RESULTS: HGV RNA in serum was found in 15 of the 23 (65%) transfusion recipients with known exposure of HGV-contaminated blood. Seven of the remaining 8 recipients showed only an anti-E2 response, indicating previous HGV infection with spontaneous clearance of the virus. In one recipient neither HGV RNA nor anti-E2 could be detected. Molecular evidence for HGV transmission by the 2 donors was found in 3 of the 6 recipients studied. The alanine aminotransferase levels were not significantly different in the HGV RNA positive and negative recipients, and none of the 23 recipients developed posttransfusion hepatitis. Persistent HGV infection was observed especially in recipients with severe hematological disorders or in those in whom intensive immunosuppressive treatment was necessary. Of the 549 individuals studied, 10 (1.8%) were healthy carriers of HGV RNA. CONCLUSION: The persistence of transfusion-acquired HGV infection is not associated with acute or chronic hepatitis, but may be influenced by the recipient's underlying disease.

Effect of hormone replacement therapy on the susceptibility of low-density lipoprotein to oxidation among postmenopausal hypercholesterolaemic women.

The effect of sequential combined hormone replacement therapy on the susceptibility of low-density lipoprotein to oxidative modification was investigated in a double-blind, randomized placebo-controlled study. Hypercholesterolaemic, postmenopausal women were supplemented with 17 beta-oestradiol and norethisterone acetate (n = 13 subjects) or placebo capsules (n = 15 subjects) for 12 weeks. They were instructed to follow the American Heart Association step one diet. Low-density lipoprotein, isolated before and after treatment, was subjected to copper-catalysed lipid peroxidation. There were no significant differences between low-density lipoprotein from the hormone replacement therapy and placebo groups, as assessed by measuring the lag time for formation of conjugated dienes, the rate of formation and the amount of conjugated dienes formed, the amount of lipid peroxides generated, and the relative electrophoretic mobility at baseline and after treatment. Dietary records showed that the subjects were consuming similar amounts of fat and vitamins. No major differences were found in the fatty acid pattern of low-density lipoprotein from the two groups. In conclusion, the results indicated that hormone replacement therapy with 17 beta-oestradiol sequentially combined with norethisterone acetate in non-smoking, hypercholesterolaemic, postmenopausal women has no protective effect on the susceptibility of low-density lipoprotein to copper-catalysed modification in vitro.

No effect of beta-carotene supplementation on the susceptibility of low density lipoprotein to in vitro oxidation among hypercholesterolaemic, postmenopausal women.

The effect of beta-carotene on the susceptibility of low density lipoprotein (LDL) to oxidative modification was investigated in a double-blind, randomized placebo-controlled study. Hypercholesterolaemic, postmenopausal women were given 30 mg beta-carotene per day (n = 15 subjects) or placebo capsules (n = 15 subjects) for 10 weeks. They were instructed to follow the American Heart Association Step One diet. LDL, isolated before and after treatment was subjected to copper-catalysed lipid peroxidation. There were no significant differences between LDL from the beta-carotene and placebo groups, as assessed by measuring the lag time for formation of conjugated dienes; the rate of formation and the amount of conjugated dienes formed; the amount of lipid peroxides generated; and the relative electrophoretic mobility, at baseline and after treatment. Dietary records showed that the subjects were consuming similar amounts and types of fat. No significant differences were found in the lipid composition and fatty acid pattern of LDL from the two groups. In conclusion, the results indicated that supplementation with beta-carotene in non-smoking, hypercholesterolaemic, postmenopausal women had no protective effect on the susceptibility of LDL to copper-catalysed modification in vitro.

Nedocromil sodium 2% eye drops for twice-daily treatment of seasonal allergic conjunctivitis: a Swedish multicentre placebo-controlled study in children allergic to birch pollen.

This was a multicentre, double-blind, randomized group comparative study in which 77 children, aged 6-16 years, received 2% nedocromil sodium eye drops and 72 received placebo, one drop into each eye twice daily. The treatment period was 4 weeks, covering the peak birch pollen season. Prior to the start of the season, patients who had attended the clinic the previous 2 years because of seasonal allergic conjunctivitis (SAC) to birch pollen, entered a one week baseline period during which symptoms were assessed, dairy cards completed, and routine sampling of blood and urine carried out. The double-blind treatment period then commenced at the onset of the birch pollen season. Patients/parents kept daily diary record cards of eye symptom severity and concomitant therapy. Conjunctivitis was mild in both treatment groups but nedocromil sodium was more effective than placebo in controlling symptoms. During the 2-3 weeks of peak pollen counts, this therapeutic effect was statistically significant for itching (P < 0.01), watering (P < 0.05) and total symptom score (P < 0.01), but was not significant for grittiness (P = 0.08) or redness (P = 0.06). Global opinions of efficacy showed no difference between treatments, due to a high placebo effect (however, the diary card data indicated a significant improvement with nedocromil sodium). We therefore conclude that nedocromil sodium 2% eye drops, administered twice daily, is an effective treatment for SAC in children.

Effect of cholesterol feeding on the susceptibility of lipoproteins to oxidative modification.

In previous studies we have shown that the liver endothelial and Kupffer cells in hypercholesterolemic rabbits are very active in endocytosis of low-density lipoprotein (LDL) and beta-very-low-density lipoprotein (beta-VLDL) (Nenseter et al. (1992) J. Lipid Res. 33, 867-877; Gudmundsen et al. (1993) J. Lipid Res. 34, 589-600). These data raised the question whether subfractions of LDL and beta-VLDL were modified in vivo to forms recognized by the scavenger/oxidized LDL receptors of the non-parenchymal liver cells. The purpose of the present study was to address this question by assessing the effect of cholesterol feeding on the susceptibility of the lipoproteins to oxidative modification in vitro. In addition, the effect of HDL on the lipid peroxidation of LDL was evaluated. LDL and beta-VLDL were isolated from rabbits given a diet supplemented with cholesterol (2% w/w) for 3 weeks. The extent of Cu(2+)-catalyzed oxidation of the lipoproteins was compared with that of LDL from control-fed rabbits. Extent of oxidation assessed by formation of conjugated dienes, lipid peroxides, thiobarbituric acid-reactive substances, relative electrophoretic mobility and uptake of lipoproteins by J774 macrophages suggested that LDL and beta-VLDL from the hypercholesterolemic rabbits were more susceptible to oxidation than LDL from normolipidemic rabbits. HDL protected LDL and beta-VLDL from lipid peroxidation in vitro. Taken together, the increased susceptibility of LDL and beta-VLDL to oxidative modification in vitro, combined with the low levels of alpha-tocopherol, and the reduced ratio of HDL to LDL cholesterol observed in the hypercholesterolemic rabbits, and the protective effect of HDL on the lipid peroxidation of LDL, support the probability that oxidative modification of LDL and beta-VLDL occur in vivo in the hypercholesterolemic rabbits.

Heparin-coated circuit during cardiopulmonary bypass. A clinical study using closed circuit, centrifugal pump and reduced heparinization.

A prospective randomized study was performed to investigate the effect of surface coating with covalently endpoint-attached heparin (Carmeda Bio Active Surface) and reduced general heparinization on haematological indices and complement C5 activation. Care was taken to optimize the rheological design of the system using centrifugal pump and a closed system without venting or machine suction. Twenty patients scheduled for aortocoronary bypass grafting (EF > 0.5) participated in the study. Ten patients were randomized to be treated with heparin-coated equipment (CBAS) and reduced i.v. heparin (1.5 mg.kg-1) while 10 patients treated with identical but noncoated equipment and full heparinization (3 mg.kg-1) served in a Control group. A vacuum suction was used to collect the blood from the operating field and it was autotransfused at weaning from extracorporeal circulation (ECC). Blood samples were obtained from the venous (precircuit) and arterial (postcircuit) side. We used a new and very specific method for detection of C5a based on monoclonal antibodies. The concentration of C5a was low in both groups during the operation but a significant increase was seen on days 1 and 2. In the Control group there was an increase from 10.2 ng.ml-1 +/- 1.2 to 27.5 ng.ml-1 +/- 4.8 on day 2 and in the CBAS group from 10.7 ng.ml-1 +/- 1.2 to 35.6 ng.ml-1 +/- 11.6 on day 2 (NS between groups). The granulocytes and total leukocyte count increased at the end of ECC and was maintained at the elevated level throughout the study period. The amount of free haemoglobin was high in the autotransfused blood in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Red glasses and visual function in retinitis pigmentosa.

UNLABELLED: As a consequence of animal reduction of the light regimes have been tried on patients with retinitis pigmentosa. The trials have been very limited and have not given reason for hope that such reduced light therapy may be beneficial. However, RP patients trying red glasses have reported acute subjective improvement of their visual function. It was the purpose of this study to try to document the reports more objectively. Five visual functions were tested with and without red glasses with the following results: 1. Visual acuity and contrast sensitivity. For one volunteer a small reproducible improvement was found. 2. Color vision. In most cases deterioration was found of already deficient color vision. 3. Visual fields. For volunteers with relatively preserved vision no difference or slight deterioration was found. For the other volunteers slight improvements were found. 4. Intraocular light scatter. No differences were found. 5. Dark adaptation. Improvements were found when the glasses were used as adaptation aid according to the method of Trendelenburg (rod function). For cone function no difference was found upon continuous wearing of red glasses. IN CONCLUSION: use of red glasses does not seem to be of great benefit as a rule. On the other hand, apart from the reduction in color discrimination no serious disadvantages seem to be inherent in their wear by RP patients.

Sexually transmitted diseases, antibodies to human immunodeficiency virus, and subsequent development of acquired immunodeficiency syndrome. Visitors of homosexual sauna clubs in Copenhagen: 1982-1983.

Sera from 260 men from Denmark and elsewhere attending two Copenhagen sauna clubs for homosexual men during nine months of 1982-1983 were investigated for markers for syphilis, hepatitis A and B, and human immunodeficiency virus (HIV). Five per cent (12 men) had active syphilis, and another 35% (92) had a history of and/or serologic markers for syphilis. Ninety-four men (36%) were positive for antibodies to hepatitis A virus, ten (4%) were positive for hepatitis B surface antigen (HBsAg), and 153 (59%) were positive for antibodies to HBsAg. Antibodies to HIV were found in 45 (20%) of the 220 men investigated for this marker. Markers for hepatitis A and B and for syphilis were more frequent in the HIV antibody-positive individuals, but the association was significant only for markers for hepatitis B (relative risk = 2.0). Thus STD markers had little predictive value for seropositivity for antibodies to HIV. Among 37 men investigated more than once, a seroconversion rate of 3% per month for antibodies to HIV was found, but this estimate must be taken with reservation. The rate of seropositivity for antibodies to HIV among men from Denmark was 23%, and three (8%) of the 40 HIV-positive Danish men developed the acquired immunodeficiency syndrome (AIDS) during the four years following the initial investigation. This study shows that by 1982-1983 HIV had spread considerably in the Danish high-risk group, although there were only seven reported cases of AIDS in the country at that time.

Clinical studies of a purified timothy pollen extract: desensitization therapy with a purified timothy pollen preparation compared to a crude timothy pollen extract. II. Results of the tests in vitro and their relation to symptoms and tests in vivo.

Perennial desensitization therapy was given during a period of 3.5 years to 40 children allergic to grass pollen allergens. 20 patients were treated with a crude and another 20 with a purified timothy pollen extract. 8 children served as untreated controls. The concentration of total and specific IgE in the treated groups covaried with those in the control group. Neither a suppression of the seasonal booster effect nor a suppression of IgE synthesis attributable to the treatment was found. The rise of timothy-specific "blocking' IgG antibodies was more pronounced in the group treated with the purified extract than in the group treated with the crude extract. A significant difference was found only after 3.5 years of treatment. The amplitude of rise of IgG antibodies correlated significantly with the effect of the treatment as judged by repeated conjunctival titration test. The results suggest that a good IgG response is an indication of successful therapy and that a better IgG response may be achieved with purified allergen extracts.

Clinical studies of a purified timothy pollen extract. Desensitization therapy with a purified timothy pollen preparation compared to a crude timothy pollen extract. I. Results of tests in vivo.

A purified freeze-dried preparation of timothy pollen was compared with a crude extract in RAST, skin tests, conjunctival provocation tests and desensitization treatment. In 48 children with grass pollen allergy a thorough allergological investigation was performed, using the two allergen preparations in different tests. The purified preparation contained relevant allergens, as judged from the good agreement between the two extracts in prick and provocation tests. The freeze-dried purified extract had good storage stability. Desensitization treatment was found to have a significant effect, as judged by repeated prick and provocation tests with both extracts. The effect of the desensitization treatment was at least as good in the children treated with the purified preparation as in those treated with the crude extract.