IL28B polymorphisms leading to poor response to treatment are associated with low necroinflammatory activity and slow fibrosis progression in HCV genotype non-1-infected patients

Background and Aims: Genetic polymorphisms near IL28Bhave been associated with spontaneous and treatment-inducedclearance of hepatitis C virus (HCV). This is believed to proceed viathe appropriate activation of innate and adaptive immune responsestargeting infected hepatocytes. Intrahepatic inflammation is thereflection of the host cell immune response, but its relationshipwith IL28B polymorphisms has yet to be fully appreciated.Methods: We analyzed the association of IL28B polymorphismswith Metavir activity (≥1) and fibrosis scores (≥2) in 1114 HCVinfectedCaucasian patients enrolled in the Swiss Hepatitis C CohortStudy (629, 127, 268 and 110 infected with HCV genotype 1, 2, 3and 4, respectively). In a subgroup of 915 patients with an estimateddate of infection, the association between IL28B polymorphismsand fibrosis progression rate (FPR > median) was assessed. Singlenucleotide polymorphisms (SNPs) of interest were extracted froma dataset generated in a genome-wide association study and/orgenotyped by TaqMan assay. Associations of alleles with differentdegrees of activity and fibrosis were evaluated using an additivemodel of inheritance by multivariate logistic regression, accountingfor all relevant covariates.Results: The rare G allele at marker rs8099917 was associated withlower activity (P = 0.008) and fibrosis (P = 0.01), as well as slower FPR(P = 0.02). Most striking associations were observed among patientsinfected with non-1 genotypes (P = 0.002 for activity, P = 0.002 forfibrosis and P = 0.005 for FPR). In genotype 1-infected patients, theassociation with activity was observed only in the recessive model(P = 0.04), whereas other associations were not significant (P = 0.7for fibrosis and P = 0.4 for FPR).Conclusions: In chronic hepatitis C, IL28B polymorphisms linkedwith a poor virological response to therapy are also associated withreduced intrahepatic necroinflammation and slower liver diseaseprogression. These observations underscore the role played by thehost immune response in clearing HCV, especially in patients withHCV genotypes non-1.

Extended treatment of treatment-naive patients with chronic hepatitis c virus (HCV) genotype 1-infection and slow response to pegylated interferon-alfa and ribavirin: a meta-analysis

Aims: Recently, several clinical trials analyzed if extended duration of treatment with pegylated interferon-alfa and ribavirin over 48 weeks can improve sustained virologic response (SVR) rates in HCV genotype 1-infected patients with slow virologic response. Because results of these clinical trials are conflicting, we performed a metaanalysis to determine the overall impact of extended treatment compared to standard treatment on virologic response rates in treatment-naive HCV genotype 1 slow responders. Methods: Literature search was performed independently by two observers using Pub Med, EMBASE, CENTRAL and abstracts presented in English at international liver and gastroenterology meetings. Randomized controlled clinical trials (RCTs; but studies that re-analyzed data retrospectively RCTs were also allowed) were considered if they included monoinfected treatment-naive HCV genotype 1 patients and compared treatment with pegIFN-alfa 2a or 2b in combination with ribavirin for 48 weeks versus extended treatment (up to 72 weeks) in slow responders. Primary and secondary end points were SVR rates and end-of-treatment (EOT) and relapse rates, respectively. In the present meta-analysis, study endpoints were summarized with a DerSimonian-Laird estimate for binary outcome basing on a random effects model. Results: Literature search yielded seven RTCs addressing the benefit of extended treatment with pegylated interferon-alfa and ribavirin in treatment-naive HCV genotype 1 slow responders. In total, 1330 slow responders were included in our meta-analysis. We show that extended treatment duration compared to the standard of care significantly improves SVR rates in HCV genotype 1 slow responders (12.4% improvement of overall SVR rate, 95% CI 0.055- 0.193, P = 0.0005). In addition, we show that rates of viral relapse were significantly reduced by extended treatment (24.1% reduction of relapse, 95% CI −0.3332 to −0.1487, P < 0.0001), whereas no significant impact of extended treatment on EOT response rates was found. Though extended treatment was burdened with an enhanced rate of premature treatment discontinuation due to interferonalfa- and ribavirin-related side effects, the frequency of serious adverse events was not increased. Conclusions: Treatment extension in HCV genotype 1 slow responders can improve SVR rates in difficult to treat patients and should be considered in patients who need to be treated before specific antivirals will be approved.

Modelling the exothermic heat and the demand of cooling in paper and pulp industry biological wastewater treatment

This master thesis presents a study on the requisite cooling of an activated sludge process in paper and pulp industry. The energy consumption of paper and pulp industry and it’s wastewater treatment plant in particular is relatively high. It is therefore useful to understand the wastewater treatment process of such industries. The activated sludge process is a biological mechanism which degrades carbonaceous compounds that are present in waste. The modified activated sludge model constructed here aims to imitate the bio-kinetics of an activated sludge process. However, due to the complicated non-linear behavior of the biological process, modelling this system is laborious and intriguing. We attempt to find a system solution first using steady-state modelling of Activated Sludge Model number 1 (ASM1), approached by Euler’s method and an ordinary differential equation solver. Furthermore, an enthalpy study of paper and pulp industry’s vital pollutants was carried out and applied to revise the temperature shift over a period of time to formulate the operation of cooling water. This finding will lead to a forecast of the plant process execution in a cost-effective manner and management of effluent efficiency. The final stage of the thesis was achieved by optimizing the steady state of ASM1.

Slow release antibiotics for treatment of septic arthritis in large animals

The search for an effective treatment for septic arthritis is ongoing. Current therapies are expensive since they require repeated joint lavage and long term antibiotic treatment. Local application of antimicrobial drugs is advantageous because high concentrations can be attained at the infection site, although repeated injections increase the risk of superinfection of the joint. Thus, slow release formulations, which have the advantage of local treatment yet single application of the drug, are appealing. Antibiotics used in slow release formulations are selected for tissue compatibility, an appropriate antibacterial spectrum, and stability both during the mixing procedure and within the carrier during the release period. Ideally the carriers should be bioresorbable. Promising reports on the clinical use of poly(methyl methacrylate) (PMMA) mixed with several different antibiotics, and of collagen sponges impregnated with gentamicin, should encourage the search for formulations optimally adapted to veterinary medical requirements.

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.

Determination Of Tetrakis(hydroxymethyl)phosphonium Sulfate In Commercial Formulations And Cooling Water By Capillary Electrophoresis With Contactless Conductivity Detection.

A novel capillary electrophoresis method using capacitively coupled contactless conductivity detection is proposed for the determination of the biocide tetrakis(hydroxymethyl)phosphonium sulfate. The feasibility of the electrophoretic separation of this biocide was attributed to the formation of an anionic complex between the biocide and borate ions in the background electrolyte. Evidence of this complex formation was provided by (11) B NMR spectroscopy. A linear relationship (R(2) = 0.9990) between the peak area of the complex and the biocide concentration (50-900 μmol/L) was found. The limit of detection and limit of quantification were 15.0 and 50.1 μmol/L, respectively. The proposed method was applied to the determination of tetrakis(hydroxymethyl)phosphonium sulfate in commercial formulations, and the results were in good agreement with those obtained by the standard iodometric titration method. The method was also evaluated for the analysis of tap water and cooling water samples treated with the biocide. The results of the recovery tests at three concentration levels (300, 400, and 600 μmol/L) varied from 75 to 99%, with a relative standard deviation no higher than 9%.

Computed tomography and scintigraphy exams for diagnosis and treatment planning of the condylar osteochondroma: a case report

PURPOSE: To report an uncommon case of osteochondroma affecting the mandibular condyle of a young patient and to illustrate the important contributions of different imaging resources to the diagnosis and treatment planning of this lesion. CASE DESCRIPTION: A 24-year-old female patient with the chief complaint of an increasing facial asymmetry and pain in the left pre-auricular region, revealing a reduced mouth opening, mandibular deviation and posterior cross-bite over a period of 18 months. Panoramic radiography revealed an enlargement of the left condyle, whereas computed tomography (CT) sections and three-dimensional CT showed a well-defined bone growth arising from condylar neck. The scintigraphy exam showed an abnormal osteogenic activity in the left temporomandibular joint. The condyle was surgically removed and after 18 months follow-up the panoramic radiography and CT scans showed no signs of recurrence. CONCLUSION: Although osteochondroma is a benign bone tumor that rarely arises in cranial and maxillofacial region, it should be considered in the differential diagnosis of slow-growing masses of the temporomandibular area and the use of different imaging exams significantly contribute to the correct diagnosis and treatment planning of this pathological condition.

Growth-active gibberellins overcome the very slow shoot growth of Hancornia speciosa, an important fruit tree from the Brazilian ""Cerrado""

Shoot elongation of Hancornia speciosa, an endangered tree from the Brazilian savannah ""Cerrado"", is very slow, thus limiting nursery production of plants. Gibberellins (GAs) A(1), A(3), and A(5), and two inhibitors of GA biosynthesis, trinexapac-ethyl and ancymidol were applied to shoots of Hancornia seedlings. GA(1) and GA(3) significantly stimulated shoot elongation, while GA(5) had no significant effect. Trinexapac-ethyl and ancymidol, both at 100 A mu g per seedling, inhibited shoot elongation up to 45 days after treatment, though the effect was statistically significant only for ancymidol. Somewhat surprisingly, exogenous GA(3) more effectively stimulated shoot elongation in SD-grown plants, than in LD-grown plants. The results from exogenous application of GAs and inhibitors of GA biosynthesis imply that Hancornia shoot growth is controlled by GAs, and that level of endogenous growth-active GAs is likely to be the limiting factor for shoot elongation in Hancornia. Application of GAs thus offer a practical method for nursery production of Hancornia seedlings for outplanting into the field.

Cutaneous Mycobacterium haemophilum infection in a kidney transplant recipient after acupuncture treatment

P>Mycobacterium haemophilum is a slow-growing nontuberculous mycobacterium that can cause disease in both immunocompetent and immunocompromised patients. The most common clinical presentations of infection are the appearance of suppurative and ulcerated skin nodules. For the diagnosis, samples collected from suspected cases must be processed under the appropriate conditions, because M. haemophilum requires lower incubation temperatures and iron supplementation in order to grow in culture. In this case report, we describe the occurrence of skin lesions in a kidney transplant recipient, caused by M. haemophilum, associated with acupuncture treatment. The diagnosis was established by direct smear and culture of material aspirated from cutaneous lesions. Species identification was achieved by characterization of the growth requirements and by partial sequencing of the hsp65 gene. The patient was successfully treated with clarithromycin and ciprofloxacin for 12 months. Considering that the number of patients receiving acupuncture treatment is widely increasing, the implications of this potential complication should be recognized, particularly in immunosuppressed patients.

alpha 1-acid glycoprotein and alpha 1-antitrypsin as early markers of treatment response in patients receiving the intensive phase of tuberculosis therapy

The identification of early markers that predict the response to anti-tuberculosis treatment would facilitate evaluation of new drugs and improve patient management. This study aimed to determine whether selected acute phase proteins and micronutrients measured at the time of diagnosis and during the first weeks of treatment could predict treatment responses during the 2-month standard intensive phase of therapy. For this purpose, alpha 1-antitrypsin, alpha 1-acid gtycoprotein, alpha 2-macroglobutin, C-reactive protein, C3, C4, zinc, copper and selenium concentrations were measured in Brazilian patients with smear-positive tuberculosis at the time of diagnosis and 1, 3, 5 and 8 weeks after initiation of therapy. Patients were classified into fast (n = 29), intermediate (n = 18) and slow responders (n = 10) if they were smear-negative at 3, 5 or 8 weeks of treatment. alpha 1-acid gtycoprotein on enrolment and 1 week of treatment, alpha 1-antitrypsin at week 1 and C-reactive protein and C3 after 3 weeks of therapy were higher in slow responders than in fast responders. alpha 1-antitrypsin and alpha 1-acid glycoprotein may be helpful in predicting treatment response at the time of initiation of therapy, and could be used as early markers to identify patients with an increased likelihood of treatment failure. (C) 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Influence of the irradiation distance and the use of cooling to increase enamel-acid resistance with Er:YAG laser

Objectives: The aim of this study was to assess the influence of irradiation distance and the use of cooling in the Er:YAG laser efficacy in preventing enamel demineralization. Methods: 84 enamel blocks were randomly assigned to seven groups (n = 12): G1: control group - no treatment, G2-G7: experimental groups treated with Er:YAG laser (80 mJ/2 Hz) at different irradiation distances with or without cooling: G2: 4 mm/2 mL; G3: 4 mm/no cooling; G4: 8 mm/2 mL; G5: 8 mm/no cooling; G6: 16 mm/2 mL; G7: 16 mm/no cooling. The samples were submitted to an in vitro pH cycles for 14 days. Next, the specimens were sectioned in sections of 80-100 mu m in thickness and the demineralization patterns of prepared slices were assessed using a polarized light microscope. Three samples from each group were analyzed with scanning electronic microscopy. Analysis of variance and the Fisher test were performed for the statistical analysis of the data obtained from the caries-lesion-depth measurements (CLDM) (alpha = 5%). Results: The control group (CLDM = 0.67 mm) was statistically different from group 2 (CLDM = 0.42 mm), which presented a smaller lesion depth, and group 6 (0.91 mm), which presented a greater lesion depth. The results of groups 3 (CLDM = 0.74 mm), 4 (CLDM = 0.70 mm), 5 (CLDM = 0.67 mm) and 7 (CLDM = 0.89 mm) presented statistical similarity. The scanning electronic microscopy analysis showed ablation areas in the samples from groups 4, 5, 6 and 7, and a slightly demineralized area in group 2. Conclusions: It was possible to conclude that Er:YAG laser was efficient in preventing enamel demineralization at a 4-mm irradiation distance using cooling. (C) 2010 Elsevier Ltd. All rights reserved.

Slow-release and organic fertilizers on early growth of Rangpur lime

Slow-release and organic fertilizers are promising alternatives to conventional fertilizers, as both reduce losses by leaching, volatilization and problems of toxicity and/or salinity to plants. The objective of this work was to evaluate the effect of different rates of the organic fertilizer Humato-Macota® compared with the slow-release fertilizer Osmocote® on the growth and nitrogen content in the dry matter of Rangpur lime. A field experiment was conducted in a factorial completely randomized design with an additional treatment (4 x 4 +1). The first factor consisted of four Humato­Macota® rates (0, 1, 2, and 3%) applied to the substrate; the second factor consisted of the same Humato-Macota® concentrations, but applied as fortnightly foliar sprays; the additional treatment consisted of application of 5 kgm-3 Osmocote® 18-05-09. Means of all growth characteristics (plant height, total dry matter, root/shoot ratio and leaf area) and the potential quantum yield of photosystem II (Fv/Fm) were higher when plants were fertilized with the slow-release fertilizer. The organic fertilizer applied alone did not meet the N requirement of Rangpur lime.

Water treatments in semi-closed cooling circuits and their impact on the quality of effluents discharged by CERN

Dissertação apresentada à Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia do Ambiente, Gestão de Sistemas Ambientais