The effect of prenatal diazepam exposure on TNF-alpha production by rat splenocytes

Prenatal exposure to diazepam and other benzodiazepines (BDZ) has been found to result in a marked reduction of T-lymphocyte proliferation during postnatal development of rats. In search for pathogenic changes underlying this effect, we investigated the mitogen lipopolysaccharide (LPS) and concanavalin A (ConA) stimulated release of tumour necrosis factor (TNF)-alpha by mixed splenocytes of male offspring from Long Evans rats treated with 1.25 mg/kg per day diazepam from gestational day 14 to 20. In response to LPS, TNF-alpha release was found to be significantly lower in mixed splenocytes of two- and four-week-old treated than in control offspring. However, at eight weeks of age, prenatally diazepam-treated animals showed a significantly higher LPS-induced TNF-alpha release than control rats. Since monocytes/macrophages represent a major source of TNF-alpha, additional experiments were performed on purified spleen macrophages and lymphocytes stimulated with LPS. TNF-alpha release was only detectable in supernatants of adherent spleen macrophages and not in supernatants of lymphocytes. Thus, our data indicate that a disturbance in TNF-alpha release from macrophages is involved in the deficient immune response of prenatally diazepam-exposed rats.     

Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B

BACKGROUND: About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. METHODS: We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. RESULTS: Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups. CONCLUSIONS: These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.     

Prevention of liquid metal embrittlement cracks in resistance spot welds by adaption of electrode geometry

ABSTRACT

Advanced high strength steels are usually coated by a zinc layer for an increased resistance against corrosion. During the resistance spot welding of zinc coated steel grades, liquid metal embrittlement (LME) may occur. As a result, cracking inside and around the spot weld indentation is observable. The extent of LME cracks is influenced by a variety of different factors. In this study, the impact of the used electrode geometry is investigated over a stepwise varied weld time. A spot welding finite element simulation is used to analyse and explain the observed effects. Results show significant differences especially for highly increased weld times. Based on identical overall dimensions, electrode geometries with a larger working plane allow for longer weld times, while still preventing LME within the investigated material and maintaining accessibility.     

Water: A key resource in energy production

Water and energy are the key resources required for both economic and population growth, and yet both are increasingly scarce. The distribution of water takes large amounts of energy, while the production of energy requires large amounts of water in processes such as thermal plant cooling systems or raw materials extraction. This study analyzes the water needs for energy production in Spain according to the energy source sector (electricity, transportation or domestic) and process type (extraction and refining of raw materials or thermal plant use). Current and future water needs are quantified according to energy demand and technology mix evolution. Hypothetical scenarios that simulate the risks of promoting specific energy policies are also analyzed. Results show that the combination of energy resources used in Spain is projected to be more than 25% more water consumptive in 2030 than in 2005 under ceteris paribus conditions. Renewable energies are mixed in terms of their consequences on the water supply; wind power can reduce water withdrawal, while the biofuels production is a water-intensive process.     

Subsurface radar signal deconvolution

We present two methods of signal deconvolution for systems whose impulse response (wavelet function) can be explicitly determined, and where the goal is to locate short impulses in the presence of strong, reverberation-like interferences.The first method, which we call algebraic deconvolution, differs from other known techniques in two ways: first of all, explicit use of the wavelet function provides more powerful a priori knowledge than the autocorrelation or the power spectrum. Secondly, this method permits to flexibly trade off noise versus resolution.In the second method presented here, we use an analytical model (synthetic wavelet) of the system impulse response to determine an inverse filter.These methods have been developed for video pulse radar signals, and encouraging early results have been obtained.     

A priori error estimates for the finite element discretization of optimal distributed control problems governed by the biharmonic operator

In this article a priori error estimates are derived for the finite element discretization of optimal distributed control problems governed by the biharmonic operator. The state equation is discretized in primal mixed form using continuous piecewise biquadratic finite elements, while piecewise constant approximations are used for the control. The error estimates derived for the state variable as well as that for the control are order-optimal on general unstructured meshes. However, on uniform meshes not all error estimates are optimal due to the low-order control approximation. All theoretical results are confirmed by numerical tests.     

Qualification test procedure for solar absorber surface durability

A general test procedure for the qualification of solar absorber surface durability has been developed based on the results of a comprehensive case study performed within the framework of the IEA Solar Heating and Cooling Programme Task X. It was assumed, in the development of the qualification procedure, that the intended use of the absorber surface to be qualified, was in single-glazed flat plate solar collectors for domestic hot water production. The absorber surface should be considered qualified if it met the requirement of a design service life of 25 years with maximum loss in the optical performance of the absorber surface corresponding to a 5% relative reduction in the performance of a solar domestic hot water system. The testing procedure, consisting of three kinds of constant load-accelerated life-time tests, was limited to simulation of the following three kinds of absorber surface degradation processes: (a) high-temperature degradation, e.g. oxidation, (b) degradation by the action of moisture or condensed water on the absorber surface, e.g. hydration or hydrolysis, and (c) degradation caused by high humidity air containing a small concentration of sulphur dioxide as an airborne pollutant, e.g. atmospheric corrosion. To quantify expected environmental stress on the absorber surface related to the environmental factors of interest, microclimate data, representing typical service conditions for absorbers in single-glazed flat plate collectors for domestic hot water production were used.     

Round robin on accelerated life testing of solar absorber surface durability

As degradation by ageing of solar absorber surfaces was identified to be an important quality factor, the Working Group MSTC (‘Materials in Solar Thermal Collectors') of the IEA-SHCP (International Energy Agency-Solar Heating and Cooling Programme) worked out a general test procedure for accelerated lifetime testing (ALT) of these materials, based on methods established by the former Task X of the IEA SHCP. The qualification test procedure was adopted by ISO and is presently dealt within ISO/TC 180 ‘Solar Energy'. The standard proposal in detail describes a procedure how to test the long-term stability of an absorber surface for the use in flat plate collectors for domestic hot water systems. The collectors service lifetime is assumed to be 25 years, at least. Degradation caused by thermal loads, high humidity and condensation and sulphur dioxide are regarded. In order to examine the feasibility and reproducibility of the test method the Working Group MSTC initiated a round robin test in accelerated life testing of solar absorber surfaces. The test was performed according to the ISO standard proposal dated January 1997. In total, five different industrially manufactured absorber coatings were available to the three participating laboratories. Tests concerning the thermal stability as well as the resistance to high humidity and condensation were performed by all three laboratories. The test for determining absorber surface corrosion resistance to air of high humidity containing sulphur dioxide was carried out by one lab only. The outcome of the round robin test shows very good agreement of the results of the different coatings tested for all of the laboratories. The feasibility and reproducibility of the method was fully confirmed.     

Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4-d]pyrimidines

In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 microM. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.