Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

Activity of tribendimidine and praziquantel combination therapy against the liver fluke Opisthorchis viverrini in vitro and in vivo

Opisthorchiasis, caused by the liver fluke Opisthorchis viverrini, a food-borne trematode, is an important public health problem; however, only a single drug, praziquantel is available. We investigated tribendimidine-praziquantel combinations against O. viverrini in vitro and in vivo. The IC50 values of 0.16μg/ml and 0.05μg/ml were determined for praziquantel and tribendimidine, respectively, against adult O. viverrini in vitro. When O. viverrini was exposed to both drugs simultaneously (using a drug ratio based on the IC50 (1:3.2)) a synergistic effect was calculated (combination index (CI) at the IC50=0.7). A similar result was observed when drug addition in vitro was spaced by the respective half-lives of the drugs (a CI of 0.78 at the IC50 for tribendimidine followed by praziquantel and a CI of 0.47 at the IC50 for praziquantel followed by tribendimidine). In vivo median-effect dose (ED50) values of 191mg/kg and 147mg/kg were calculated for praziquantel and tribendimidine, respectively. Low to moderate worm burden reductions (38-62%) were observed in O. viverrini infected hamsters when both drugs were administered simultaneously or on subsequent days, pointing to antagonistic effects in vivo. Further studies are necessary to understand the striking differences between the in vitro and in vivo observations using combinations of praziquantel and tribendimidine on O. viverrin

Advanced Modeling and Materials in Kraft Pulp Mills

This CRADA provided technical support to the Weyerhaeuser Company on a number of issues related to the performance and/or selection of materials at a number of locations in a pulp and paper mill. The studies related primarily to components for black liquor recovery boilers, but some effort was directed toward black liquor gasifiers and rolls for paper machines. The purpose of this CRADA was to assist Weyerhaeuser in the evaluation of materials exposed in various paper mill environments and to provide direction in the selection of alternate materials, when appropriate

Evaluation of Clinical and Immunological Markers for predicting Virological Failure in a HIV/AIDS treatment cohort in Busia, Kenya

In resource-limited settings where viral load (VL) monitoring is scarce or unavailable, clinicians must use immunological and clinical criteria to define HIV virological treatment failure. This study examined the performance of World Health Organization (WHO) clinical and immunological failure criteria in predicting virological failure in HIV patients receiving antiretroviral therapy (ART)

Albatrellus confluens (Alb. & Schwein.) Kotl. & Pouz.: natural fungal compounds and synthetic derivatives with in vitro anthelmintic activities and antiproliferative effects against two human cancer cell lines

Neglected tropical diseases affect the world's poorest populations with soil-transmitted helminthiasis and schistosomiasis being among the most prevalent ones. Mass drug administration is currently the most important control measure, but the use of the few available drugs is giving rise to increased resistance of the parasites to the drugs. Different approaches are needed to come up with new therapeutic agents against these helminths. Fungi are a source of secondary metabolites, but most fungi remain largely uninvestigated as anthelmintics. In this report, the anthelmintic activity of Albatrellus confluens against Caenorhabditis elegans was investigated using bio-assay guided isolation. Grifolin (1) and neogrifolin (2) were identified as responsible for the anthelmintic activity. Derivatives 4-6 were synthesized to investigate the effect of varying the prenyl chain length on anthelmintic activity. The isolated compounds 1 and 2 and synthetic derivatives 4-6, as well as their educts 7-10, were tested against Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum. Prenyl-2-orcinol (4) and geranylgeranyl-2-orcinol (6) showed promising activity against newly transformed schistosomula. The compounds 1, 2, 4, 5, and 6 were also screened for antiproliferative or cytotoxic activity against two human cancer lines, viz. prostate adenocarcinoma cells (PC-3) and colorectal adenocarcinoma cells (HT-29). Compound 6 was determined to be the most effective against both cell lines with IC50 values of 16.1 microM in PC-3 prostate cells and 33.7 microM in HT-29 colorectal cells

Efficacy and Safety of Artemether in the Treatment of Chronic Fascioliasis in Egypt: Exploratory Phase-2 Trials

Fasciola hepatica and F. gigantica are two liver flukes that parasitize herbivorous large size mammals (e.g., sheep and cattle), as well as humans. A single drug is available to treat infections with Fasciola flukes, namely, triclabendazole. Recently, laboratory studies and clinical trials in sheep and humans suffering from acute fascioliasis have shown that artesunate and artemether (drugs that are widely used against malaria) also show activity against fascioliasis. Hence, we were motivated to assess the efficacy and safety of oral artemether in patients with chronic Fasciola infections. The study was carried out in Egypt and artemether administered according to two different malaria treatment regimens. Cure rates observed with 6×80 mg and 3×200 mg artemether were 35% and 6%, respectively. In addition, high efficacy was observed when triclabendazole, the current drug of choice against human fascioliasis, was administered to patients remaining Fasciola positive following artemether treatment. Concluding, monotherapy with artemether does not represent an alternative to triclabendazole against fascioliasis, but its role in combination chemotherapy regimen remains to be investigated

Improved Materials for High-Temperature Black Liquor Gasification

The laboratory immersion test system built and operated at ORNL was found to successfully screen samples from numerous refractory suppliers, including both commercially available and experimental materials. This system was found to provide an accurate prediction of how these materials would perform in the actual gasifier environment. Test materials included mullites, alumino-silicate bricks, fusion-cast aluminas, alumina-based and chrome-containing mortars, phosphate-bonded mortars, coated samples provided under an MPLUS-funded project, bonded spinels, different fusion-cast magnesia-alumina spinels with magnesia content ranging from 2.5% to about 60%, high-MgO castable and brick materials, spinel castables, and alkali-aluminate materials. This testing identified several candidate material systems that perform well in the New Bern gasifier. Fusion-cast aluminas were found to survive for nearly one year, and magnesia-alumina spinels have operated successfully for 18 months and are expected to survive for two years. Alkali-aluminates and high-MgO-content materials have also been identified for backup lining applications. No other material with a similar structure and chemical composition to that of the fusion-cast magnesium-aluminum spinel brick currently being used for the hot-face lining is commercially available. Other materials used for this application have been found to have inferior service lives, as previously discussed. Further, over 100 laboratory immersion tests have been performed on other materials (both commercial and experimental), but none to date has performed as well as the material currently being used for the hot-face lining. Operating experience accumulated with the high-temperature gasifier at New Bern, North Carolina, has confirmed that the molten alkali salts degrade many types of refractories. Fusion-cast alumina materials were shown to provide a great improvement in lifetime over materials used previously. Further improvement was realized with fusion-cast magnesia-alumina spinel refractory, which appears to be the most resistant to degradation found to date, exhibiting over a year of service life and expected to be capable of over two years of service life. Regarding the use of refractory mortar, it was found that expansion of the current chrome-alumina mortar when subjected to black liquor smelt is likely contributing to the strains seen on the vessel shell. Additionally, the candidate high-alumina mortar that was originally proposed as a replacement for the current chrome-alumina mortar also showed a large amount of expansion when subjected to molten smelt. A UMR experimental mortar, composed of a phosphate bonded system specifically designed for use with fusion-cast magnesium-aluminum spinel, was found to perform well in the molten smelt environment. Strain gauges installed on the gasifier vessel shell provided valuable information about the expansion of the refractory, and a new set of strain gauges and thermocouples has been installed in order to monitor the loading caused by the currently installed spinel refractory. These results provide information for a direct comparison of the expansion of the two refractories. Measurements to date suggest that the fusion-cast magnesia-alumina spinel is expanding less than the fusion-cast {alpha}/{beta}-alumina used previously. A modified liquor nozzle was designed and constructed to test a number of materials that should be more resistant to erosion and corrosion than the material currently used. Inserts made of three erosion-resistant metallic materials were fabricated, along with inserts made of three ceramic materials. The assembled system was sent to the New Bern mill for installation in the gasifer in 2005. Following operation of the gasifier using the modified nozzle, inserts should be removed and analyzed for wear by erosion/corrosion. Although no materials have been directly identified for sensor/thermocouple protection tubes, several of the refractory material systems identified for lining material applications may be applicable for use in this capacity. Results of the modeling studies suggest that the temperature distribution is higher at the bottom of the gasifier than previously thought. Therefore, it may be possible to reduce the refractory temperature in the gasifier by changing the liquor spray. Also, modeling showed that because of the strong swirl, a separation zone could be formed at the corner of the conical wall where it meets the vertical barrel wall, and some the liquor droplets could be suspended in this zone. The accumulation of droplets in this area could cause instabilities in the performance and also in corrosion of the refractory

Quantum measurement problem and cluster separability

A modified Beltrametti-Cassinelli-Lahti model of measurement apparatus that satisfies both the probability reproducibility condition and the objectification requirement is constructed. Only measurements on microsystems are considered. The cluster separability forms a basis for the first working hypothesis: the current version of quantum mechanics leaves open what happens to systems when they change their separation status. New rules that close this gap can therefore be added without disturbing the logic of quantum mechanics. The second working hypothesis is that registration apparatuses for microsystems must contain detectors and that their readings are signals from detectors. This implies that separation status of a microsystem changes during both preparation and registration. A new rule that specifies what happens at these changes and that guarantees the objectification is formulated and discussed. A part of our result has certain similarity with 'collapse of the wave function'.Comment: 31 pages, no figure. Published versio