A non-interventional phase IV Belgian survey to assess the antiviral effectiveness of pegylated interferon-alpha-2b and ribavirin treatment according to the stage of liver fibrosis in previously untreated patients with genotype 1/4/5/6 chronic hepatitis C (PRACTICE).

BACKGROUND AND STUDY AIMS: This was an observational, non-interventional, multicenter, phase IV study, in patients with genotype 1/4/5/6 chronic hepatitis C (CHC). The primary objectives were to evaluate SVR in patients with no or minimal fibrosis (METAVIR F0-F1) versus well established fibrosis (F2-F4), and to estimate response on Weeks 12, 24 and 48 on treatment in previously untreated patients with genotypes 1/4/5/6 CHC. PATIENTS AND METHODS: 538 patients treated with pegylated interferon alfa 2b 1.5 mcg/kg in combination with ribavirin 800-1200 mg/day were enrolled in 55 sites in Belgium and Luxembourg, 505 being considered for the analysis. 40% of the patients were female and 60% male, the average age was 47.5 years, 10.5% were 65 or older. RESULTS: SVR was observed in 35% of the patients, EVR in 68%, of which pEVR in 33% and cEVR in 35%. SVR was observed in 43% of the low fibrosis group (F0, F1) and 30% of the high fibrosis group (F2, F3, F4) (p = 0.005). SVR rates were 34% for genotype 1, 37% for genotype 4, and 47% for genotype 5 (NS). Multivariate analysis showed that EVR and baseline METAVIR score are independent prognostic factors for SVR. CONCLUSIONS: This trial confirms that fibrosis stage and early viral response are the most important key-factors to predict sustained response, suggesting that the earlier patients are treated, the better the outcome. Non-invasive techniques enable us to closely monitor progression of fibrosis, allowing a better selection of patients for antiviral treatment in the DAA-era.

Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy.

Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels. Conclusion: In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.

Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients.

SUMMARY: Reluctance has been expressed about treating chronic hepatitis C in active intravenous (IV) drug users (IDUs), and this is found in both international guidelines and routine clinical practice. However, the medical literature provides no evidence for an unequivocal treatment deferral of this risk group. We retrospectively analyzed the direct effect of IV drug use on treatment outcome in 500 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study. Patients were eligible for the study if they had their serum hepatitis C virus (HCV) RNA tested 6 months after the end of treatment and at least one visit during the antiviral therapy, documenting the drug use status. Five hundred patients fulfilled the inclusion criteria (199 were IDU and 301 controls). A minimum exposure to 80% of the scheduled cumulative dose of antivirals was reached in 66.0% of IDU and 60.5% of controls (P = NS). The overall sustained virological response (SVR) rate was 63.6%. Active IDU reached a SVR of 69.3%, statistically not significantly different from controls (59.8%). A multivariate analysis for treatment success showed no significant negative influence of active IV drug use. In conclusion, our study shows no relevant direct influence of IV drugs on the efficacy of anti-HCV therapy among adherent patients.

Origin of mineralizing fluids of the sediment-hosted Navachab gold mine, Namibia: Constraints from stable (O, H, C, S) isotopes

The Navachab gold mine in the Damara belt of central Namibia is characterized by a polymetallic Au-Bi-As-Cu-Ag ore assemblage, including pyrrhotite, chalcopyrite, sphalerite, arsenopyrite, bismuth, gold, bismuthinite, and bismuth tellurides. Gold is hosted by quartz sulfide veins and semimassive sulfide lenses that are developed in a near-vertical sequence of shelf-type metasedimentary rocks, including marble, calcsilicate rock, and biotite schist. The sequence has been intruded by abundant syntectonic lamprophyre, aplite, and pegmatite dikes, documenting widespread igneous activity coeval with mineralization. The majority of quartz from the veins has delta(18)O values of 14 to 15 per mil (V-SMOW). The total variations in delta(18)O values of the biotite schist and calcsilicate rock are relatively small (12-14 parts per thousand), whereas the marble records steep gradients in delta(18)O values (17-21 parts per thousand), the lowest values being recorded at the vein margins. Despite this, there is no correlation between delta(18)O and delta(13)C values and the carbonate content of the rocks, indicating that fluid-rock interaction alone cannot explain the isotopic gradients. In addition, the marble records increased delta(13)C values at the contact to the veins, possibly related to a change in the physicochemical conditions during fluid-rock interaction. Gold is interpreted to have precipitated in equilibrium with metamorphic find (delta(18)O 12-14 parts per thousand; delta D = -40 to -60 parts per thousand) at peak metamorphic conditions of ca. 550 degrees C and 2 kbars, consistent with isotopic fractionations between coexisting calcite, garnet, and clinopyroxene in the alteration halos. The most likely source of the mineralizing fluid was a midcrustal fluid in equilibrium with the Damaran metapelites that underwent prograde metamorphism at amphibolite- to granulite-facies grades. Although there is no isotopic evidence for the contribution of magmatic fluids, they may have been important in contributing to the overall hydraulic regime and high apparent geothermal gradients (ca. 80 degrees C/km(-1)) in the mine area.

Physical activity modulates heat shock protein-72 expression and limits oxidative damage accumulation in a healthy elderly population aged 60 90 years

BACKGROUND: Reactive oxygen species production increases during aging, whereas protective mechanisms such as heat shock proteins (HSPs) or antioxidant capacity are depressed. Physical activity has been hypothesized to provide protection against oxidative damage during aging, but results remain controversial. This study aimed to investigate the effect of different levels of physical activity during aging on Hsp72 expression and systemic oxidative stress at rest and in response to maximal exercise. METHODS: Plasma antioxidant capacity (Trolox equivalent antioxidant capacity, TEAC), thiobarbituric acid-reactive species (TBARS), advanced oxidized proteins products (AOPP), and Hsp72 expression in leukocytes were measured before and after maximal exercise testing in 32 elderly persons (aged 73.2 years), who were assigned to two different groups depending on their level of physical activity during the past 12 months (OLow = moderate to low level; OHigh = higher level). RESULTS: The OHigh group showed higher aerobic fitness and TEAC (both representing 120% of OLow values) as well as lower oxidative damage (50% of OLow values) and Hsp72 expression. Exercise led to a lower increase in oxidative damage in the OHigh group. Aerobic fitness was positively correlated with TEAC and negatively with lipid peroxidation (TBARS). Hsp72 expression was negatively correlated with TEAC but positively correlated with TBARS levels. CONCLUSIONS: The key finding of this study is that, in people aged 60 to 90 years, long-term high level of physical activity preserved antioxidant capacity and limited oxidative damage accumulation. It also downregulated Hsp72 expression, an adaptation potentially resulting from lower levels of oxidative damage.

Vitamin C requirements in parenteral nutrition.

Some biochemical functions of vitamin C make it an essential component of parenteral nutrition (PN) and an important therapeutic supplement in other acute conditions. Ascorbic acid is a strong aqueous antioxidant and is a cofactor for several enzymes. The average body pool of vitamin C is 1.5 g, of which 3%-4% (40-60 mg) is used daily. Steady state is maintained with 60 mg/d in nonsmokers and 140 mg/d in smokers. Shocked surgical, trauma, and septic patients have a drastic reduction of circulating plasma ascorbate concentrations. These low concentrations require 3-g doses/d to restore normal plasma ascorbate concentrations, questioning the recommended PN dose of 100 mg/d. Determination of intravenous requirements is usually based on plasma concentrations, which are altered during the inflammatory response. There is no clear indicator of deficiency: serum or plasma ascorbate concentrations <0.3 mg/dL (20 micromol/L) indicates inadequate vitamin C status. On the basis of available pharmacokinetic data the 100 mg/d dose for patients receiving home PN and 200 mg/d for stable adult patients receiving PN are adequate, but requirements have been shown to be higher in perioperative, trauma, burn, and critically ill patients, paralleling oxidative stress. One recommendation cannot fit all categories of patients. Large vitamin C supplements may be considered in severe critical illness, major trauma, and burns because of increased requirements resulting from oxidative stress and wound healing. Future research should distinguish therapeutic use of high-dose ascorbic acid antioxidant therapy from nutritional PN requirements.

Biomassa microbiana e produção de C-CO2 e N mineral de um podzólico vermelho-escuro submetido a diferentes sistemas de manejo: Microbial biomass and C-CO2 and mineral nitrogen production in paleudult soil cultivated under different management systems

Os sistemas de manejo, com diferenças no revolvimento do solo e na composição dos resíduos vegetais, alteram as propriedades biológicas do solo, com reflexos na qualidade do solo e na produtividade das culturas. Com vistas em medir estas alterações nas propriedades biológicas do solo, a biomassa e a atividade microbiana foram avaliadas em um Podzólico Vermelho-Escuro, em Eldorado do Sul (RS), utilizando diferentes preparos (convencional, reduzido e plantio direto) e dois sistemas de sucessões de culturas (aveia preta + vica/milho + caupi e aveia/milho). As avaliações foram realizadas em quatro épocas, durante 12 meses, e em duas profundidades (0-5 e 5-15 cm). O carbono da biomassa microbiana foi analisado pelo método de fumigação-incubação, e a atividade microbiana, pela produção de C-CO2 e N mineral, após 60 dias de incubação. As diferenças na biomassa e na atividade microbiana, entre os sistemas de manejo, foram mais pronunciadas na camada de 0-5 cm. Nesta camada de solo, observaram-se os maiores valores de biomassa e de atividade nos preparos conservacionistas e no sistema aveia + vica/milho + caupi. Dentre as variáveis estudadas, a mineralização de N mostrou-se a mais sensível aos manejos, à profundidade e à época de amostragem.

Mineralização do C e do N em amostras armazenadas de solo cultivado com cana-de-açúcar, ao longo de dez anos, com e sem fertilização nitrogenada

As taxas de mineralização do C e do N foram estimadas em amostras de um Podzólico Vermelho-Amarelo latossólico álico textura arenosa, retiradas nas profundidades de 0-20, 20-40 e 40-60 cm, ao longo dos 10 anos de um experimento de campo com cana-de-açúcar, de parcelas com e sem fertilização nitrogenada (60 kg ha-1 de N na forma de uréia). A mineralização do N foi medida por meio da técnica de incubação com percolação periódica e a do C pela quantidade de C-CO2 absorvida em solução de NaOH 1 mol L-1, por titulação potenciométrica. Em geral, apenas na camada superficial, o N total mineralizado acumulado durante as 20 semanas de incubação foi maior, 13% a mais no tratamento fertilizado que no não fertilizado. Entre épocas de amostragem, ao longo dos 10 anos, dentro de cada tratamento, houve diferenças significativas nas três profundidades. No entanto, as épocas de maiores mineralizações não foram as mesmas para todas as profundidades e tratamentos e não mostraram nenhuma tendência mais consistente. O C total mineralizado não diferiu significativamente entre os tratamentos (fertilizado e não fertilizado). As curvas de mineralização de C seguiram uma tendência mais linear que as do N, indicando uma possível estabilização nas taxas de mineralização entre 8 e 20 semanas. Os valores de produção média de C e N mineralizados foram de 611 e 26, 411 e 17 e 427 e 15 mg kg-1 de solo, para as profundidades de 0-20, 20-40 e 40-60 cm, respectivamente. O resultado mais importante foi a manutenção do potencial de mineralização de N do solo ao longo dos 10 anos de cultivo com cana, mesmo nas amostras provenientes das parcelas sem fertilização.

Cultivo consorciado de aveia e ervilhaca: relação C/N da fitomassa e produtividade do milho em sucessão

A aveia e a ervilhaca são as principais culturas de cobertura de solo utilizadas durante o inverno na região sul do Brasil. O cultivo consorciado dessas duas espécies, estratégia ainda pouco utilizada, pode potencialmente resultar numa fitomassa com relação C/N mais equilibrada do que aquela proveniente das culturas solteiras, bem como proporcionar resíduos culturais que atuem, simultaneamente, na proteção do solo contra os agentes erosivos e no suprimento de N ao milho. Com o objetivo de avaliar esta hipótese, realizou-se este trabalho, durante o ano agrícola de 1992/93, em área do Departamento de Solos da Universidade Federal de Santa Maria, num Argissolo Vermelho distrófico arênico (Hapludalf). Os tratamentos constaram de diferentes proporções de densidade de semeadura de ervilhaca comum (E) e aveia preta (A): T1: 100% E (80 kg ha-1de sementes); T2: 90% E (72 kg ha-1) + 10% A (8 kg ha-1); T3: 75% E (60 kg ha-1) + 25% A (20 kg ha-1); T4: 50% E (40 kg ha-1) + 50% A (40 kg ha-1); T5: 25% E (20 kg ha-1) + 75% A (60 kg ha-1) e T6: 100% A (80 kg ha-1). Além desses, foram utilizados dois tratamentos, nos quais o solo permaneceu em pousio durante o inverno: no primeiro tratamento, foram aplicados 75 kg ha-1 de N-uréia no milho (T7) e, no segundo, a cultura foi plantada sem adubação nitrogenada (T8). Em sucessão à ervilhaca como cultura solteira, com relação C/N de 13,5, a produtividade de grãos de milho chegou a 5,44 t ha-1, não diferindo do tratamento em pousio com aplicação de N-uréia. Todavia, a ervilhaca foi rapidamente decomposta e, seis meses após o seu manejo, apenas 19,5% da fitomassa inicial encontrava-se na superfície do solo. Com a inclusão da aveia em consórcio com a ervilhaca ocorreu um aumento gradativo na relação C/N da fitomassa, diminuindo o fornecimento de N ao milho e aumentando a persistência dos resíduos culturais. O consórcio que apresentou melhor equilíbrio entre produção de fitomassa, proteção do solo pelos resíduos culturais e fornecimento de N ao milho foi o que continha 10% de aveia + 90% de ervilhaca (relação C/N = 18,6).

Razão de perdas de terra e fator C da cultura do cafeeiro em cinco espaçamentos, em Pindorama (SP)

hídrica em culturas perenes, embora tais dados sejam imprescindíveis ao planejamento conservacionista e estudos de modelagem de erosão. Dados de um experimento de perdas de terra e água sob chuva natural em Pindorama (SP), de julho de 1960 a junho de 1972, foram usados para o cálculo da razão de perdas de terra (RPT) e do fator C da equação universal de perdas de solo, em cinco espaçamentos na cultura do cafeeiro (Coffea arabica L.). Foram estabelecidas parcelas com espaçamentos de 3,0 x 0,5 m, 3,0 x 1,0 m, 3,0 x 2,0 m, 3,0 x 3,0 m e 4,0 x 2,0 m em um Argissolo Vermelho-Amarelo eutrófico textura arenosa/média com declividade média de 0,100 m m-1. O ciclo da cultura foi dividido em dois estádios: do plantio aos 60 meses e dos 60 aos 144 meses. Os resultados mostraram que: (a) as perdas anuais de terra e água para a cultura do cafeeiro foram de 4 Mg ha-1 e 18 mm respectivamente; (b) os valores de RPT para o cafeeiro foram de 0,1346, 0,0883, 0,1015, 0,1422 e 0,1001 Mg ha-1 Mg-1 ha, para os espaçamentos 3,0 x 0,5 m, 3,0 x 1,0 m, 3,0 x 2,0 m, 3,0 x 3,0 m e 4,0 x 2,0 m respectivamente; (c) a magnitude do fator C, para os referidos espaçamentos, foi, respectivamente, de 0,1354, 0,0866, 0,0995, 0,1412 e 0,1004 Mg ha-1 Mg-1 ha; (d) as RPTs e os fatores C variaram amplamente entre os espaçamentos, bem como e, mais expressivamente, entre os estádios da cultura, indicando forte efeito do espaçamento e da cobertura vegetal; (e) o espaçamento 3,0 x 1,0 mostrou-se mais eficiente na redução da erosão hídrica na cultura do cafeeiro.

High prevalence of osteoporosis in Swiss women aged 60 and older: a 2-year pilot screening campaign.

Background: Osteoporosis (OP) is frequent in postmenopausal women, but remains underdiagnosed and undertreated. In Switzerland, DXA is not reimbursed by the insurances for screening, even if it is recommended to test women's Bone Mineral Density (BMD) at the age of 65. Methods: To assess the feasibility of a screening program for OP, the Bone diseases center of Lausanne has been mandated to perform a 2-year information and screening campaign (3 days per months) for women age 60 and older through the state of Vaud using a mobile unit for bone assessment. This project is still ongoing. Women are informed by media for dates and screening locations. Appointments are taken by phone. Women known for osteoporosis or already treated are excluded. During the evaluation every women is assessed by a questionnaire for risk factors, by a DXA measurement (Discovery C, Hololgic), and by Vertebral Fracture Assessment (VFA) for Genant's grades 2 and 3 prevalent vertebral fractures (VF). Women are considered at high risk of fracture if they have a hip fracture, a VF, another fragility fracture with a BMD T-score ≤-2 or a BMD T-score ≤-2.5. Results: After 17 months (50 days of screening), 752 women were assessed, mean age 66±6 yrs, mean BMI 26±5 kg/m2, mean lowest T-score -1.6±1.0 SD. 215 women (29%) were considered at high risk, 92 of them (12%) having established OP and 50 (7%) having one or more fragility VF. VF were unknown for 83% of the women and discovered by VFA. The number needed to screen (NNS) were 3.5 for high risk women, 8.2 for established OP and 15 for VF. Conclusions: After near ¾ of the project, prevalence of women at high risk of fracture was high, with a NNS below 4. Knowing the global cost of OP and that current treatment have a high efficacy for fracture risk reduction, such a screening program could have a positive economic impact. VFA allowed discovering many women with unknown VF, who were at very high risk of further fractures. A systematic screening for VF should be added to BMD measurements after the age of 60.

Elderly age is not a negative predictive factor for virological response to therapy with pegylated interferon-α and ribavirin in chronic hepatitis C virus patients.

BACKGROUND & AIMS: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral therapy of chronic hepatitis C. However, elderly patients often show advanced fibrosis/cirrhosis as known negative predictive factor. The aim of this study was to assess age as an independent predictive factor during antiviral therapy. METHODS: Overall, 516 hepatitis C patients were treated with pegylated interferon-α and ribavirin, thereof 66 patients ≥60 years. We analysed the impact of host factors (age, gender, fibrosis, haemoglobin, previous hepatitis C treatment) and viral factors (genotype, viral load) on SVR per therapy course by performing a generalized estimating equations (GEE) regression modelling, a matched pair analysis and a classification tree analysis. RESULTS: Overall, SVR per therapy course was 42.9 and 26.1%, respectively, in young and elderly patients with hepatitis C virus (HCV) genotypes 1/4/6. The corresponding figures for HCV genotypes 2/3 were 74.4 and 84%. In the GEE model, age had no significant influence on achieving SVR. In matched pair analysis, SVR was not different in young and elderly patients (54.2 and 55.9% respectively; P = 0.795 in binominal test). In classification tree analysis, age was not a relevant splitting variable. CONCLUSIONS: Age is not a significant predictive factor for achieving SVR, when relevant confounders are taken into account. As life expectancy in Western Europe at age 60 is more than 20 years, it is reasonable to treat chronic hepatitis C in selected elderly patients with relevant fibrosis or cirrhosis but without major concomitant diseases, as SVR improves survival and reduces carcinogenesis.