Background. A human immunodeficiency virus (HIV) vaccine that limits disease and transmission is urgently needed. This clinical trial evaluated the safety and immunogenicity of an HIV vaccine that ...combines a plasmid-DNA priming vaccine and a modified vaccinia virus Ankara (MVA) boosting vaccine. Methods. Forty healthy volunteers were injected with DNA plasmids containing gp160 of HIV-1 subtypes A, B, and C; rev B; p17/p24 gag A and B, and RTmut B by use of a needle-free injection system. The vaccine was administered intradermally or intramuscularly, with or without recombinant granulocyte macrophage colony-stimulating factor, and boosted with a heterologous MVA containing env, gag, and pol of CRF01A_E. Immune responses were monitored with HIV-specific interferon (IFN)-γ and interleukin (IL)-2 ELISpot and lymphoproliferative assays (LPAs). Results. Vaccine-related adverse events were mild and tolerable. After receipt of the DNA priming vaccine, 11 (30%) of 37 vaccinees had HIV-specific IFN-γ responses. After receipt of the MVA boosting vaccine, ELISpot assays showed that 34 (92%) of 37 vaccinees had HIV-specific IFN-γ responses, 32 (86%) to Gag and 24 (65%) to Env. IFN-γ production was detected in both the CD8+ T cell compartment (5 of 9 selected vaccinees) and the CD4+ T cell compartment (9 of 9). ELISpot results showed that 25 (68%) of 37 vaccinees had a positive IL-2 response and 35 (92%) of 38 had a positive LPA response. Of 38 subjects, a total of 37 (97%) were responders. One milligram of HIV-1 DNA administered intradermally was as effective as 4 mg administered intramuscularly in priming for the MVA boosting vaccine. Conclusion. This HIV-DNA priming-MVA boosting approach is safe and highly immunogenic. Trials registration. International Standard Randomised Controlled Trial number: ISRCTN32604572.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The conformational dependence of the electronic absorption by astaxanthin is believed to be of relevance for the bathochromic shift that this carotenoid assumes upon binding to crustacyanin, the ...protein macromolecular complex responsible for the slate-blue colouration of lobster shell. Here, we report quantum chemical calculations suggesting that the bathochromic shift that can be attributed to changes in astaxanthin conformation brought about by binding to the protein in fact is rather small. In particular, by subjecting an exhaustive set of different astaxanthin conformations to time-dependent density functional theory (TD-DFT) and semiempirical configuration interaction singles (ZINDO/S) calculations, it is found that the bathochromic shift due to the protein-enforced coplanarity of the β-ionone rings with the polyene chain is considerably smaller (TD-DFT: 22–37 nm; ZINDO/S: 11–19 nm) than the >100 nm shift that recently B. Durbeej and L. A. Eriksson, Chem. Phys. Lett. , 2003, 375 , 30 was predicted to arise from a hydrogen-bond mediated interaction involving one of the astaxanthin C4 keto groups and a histidine residue of the surrounding protein. Moreover, the calculations suggest that the protein-induced bowing of astaxanthin about the center of the polyene chain is of no relevance for the observed bathochromic shift.
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Objectives. Venous thromboembolism (VTE) is a potentially serious complication of hospitalization and immobilization. The use of anticoagulant prophylaxis in acutely ill medical inpatients is ...still under debate. New data including a recent meta‐analysis have recently been published. We aim at studying the efficacy and safety of anticoagulant prophylaxis in acutely ill medical inpatients, and demonstrate differences between meta‐analyses due to different data extraction from the heterogeneous studies included.
Subjects. The Cochrane Library, MEDLINE and EMBASE were searched from 1980 to present. Manual searches were performed regarding s from major meetings. Seven blinded randomized controlled clinical trials assessing the prophylactic effect of heparin in acutely ill medical patients were identified and included in the meta‐analysis.
Results. Low‐molecular weight heparin (LMWH) prophylaxis prevented 48% of symptomatic pulmonary embolism (PE), 48% of symptomatic deep vein thrombosis (DVT) (not significant) and 51% of asymptomatic DVT. A nonsignificant trend towards higher bleeding risk during LMWH prophylaxis was found. Death was not significantly affected. We compared our data with a recent meta‐analysis with different study selection and data extraction and found similar results.
Conclusions. As DVT and PE are manifestations of the same illness, VTE, one can argue that anticoagulant prophylaxis prevents approximately half of the expected events. Most medical inpatients have short hospital stays, and a low risk of VTE. The important task for the clinician is to identify patients with a sufficiently high risk of symptomatic VTE to warrant LMWH prophylaxis. Despite differences in study selection and data extraction, our study shows results similar to a recent meta‐analysis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: Women who smoke have higher risk of lung function impairment, COPD and lung cancer than smoking men. An influence of sex hormones has been demonstrated, but the mechanisms are unclear and ...the associations often subject to confounding. This was a study of wheeze in relation to smoking and sex with adjustment for important confounders.
Methods: In 2008 the Global Allergy and Asthma European Network (GA 2 LEN) questionnaire was mailed to 45.000 Swedes (age 16–75 years), and 26.851 (60%) participated. “Any wheeze”: any wheeze during the last 12 months. “Asthmatic wheeze”: wheeze with breathlessness apart from colds.
Results: Any wheeze and asthmatic wheeze was reported by 17.3% and 7.1% of women, vs. 15.8% and 6.1% of men (both p<0.001). Although smoking prevalence was similar in both sexes, men had greater cumulative exposure, 16.2 pack-years vs. 12.8 in women (p<0.001). Most other exposures and characteristics associated with wheeze were significantly overrepresented in men. Adjusted for these potential confounders and pack-years, current smoking was a stronger risk factor for any wheeze in women aged <53 years, adjusted odds ratio (aOR) 1.85 (1.56–2.19) vs. 1.60 (1.30–1.96) in men. Cumulative smoke exposure and current smoking each interacted significantly with female sex, aOR 1.02 per pack-year (p<0.01) and aOR 1.28 (p = 0.04) respectively. Female compared to male current smokers also had greater risk of asthmatic wheeze, aOR 1.53 vs. 1.03, interaction aOR 1.52 (p = 0.02). These interactions were not seen in age ≥53 years.
Discussion: In addition to the increased risk of COPD and lung cancer female, compared to male, smokers are at greater risk of significant wheezing symptoms in younger age. This became clearer after adjustment for important confounders including cumulative smoke exposure. Estrogen has previously been shown to increase the bioactivation of several compounds in tobacco smoke, which may enhance smoke-induced airway inflammation in fertile women.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that ...MTTP influences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/EBP binds to the polymorphic region in an allele-specific manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hydrogen abstraction from the C1' and C2' positions of deoxyadenosine by a neighbouring uracil-5-yl radical in the 5'-AU*-3' DNA sequence is explored using DFT. This hydrogen abstraction is the first ...step in a sequence leading to single or double strand break in DNA. The uracil-5-yl radical can be the result of photolysis or low-energy electron (LEE) attachment. If the radical is produced by photolysis the neighbouring adenine will become a cation radical and if it is produced by LEE the adenine will remain neutral. The hydrogen abstraction reactions for both cases were investigated. It is concluded that it is possible for the uracil-5-yl to abstract hydrogen from C1' and C2'. When adenine is neutral there is a preference for the C1' site and when the adenine is a radical cation the C2' site is the preferred. If adenine is positively charged, the rate-limiting step when abstracting hydrogen from C1' is the formation of an intermediate crosslink between uracil and adenine. This crosslink might be avoided in dsDNA, making C1' the preferred site for abstraction.
Apolipoprotein (apo) A-I is the major protein component of HDL, a cholesterol transport particle that protects against atherosclerosis. Apo A-I is believed to promote reverse cholesterol transport, ...transferring cholesterol from peripheral cells to the liver for subsequent elimination. To test this hypothesis in humans, we measured fecal steroid excretion before and after the intravenous infusion of human proapo A-I (precursor of apo A-I) liposome complexes.
Four subjects with heterozygous familial hypercholesterolemia w re studied under standardized conditions. The fecal excretion of bile acids and neutral sterols was determined for 9 days before and 9 days after an intravenous infusion of recombinant human proapo A-I (4 g protein) liposome complexes. Plasma apoA-I and HDL cholesterol levels increased transiently (mean peak concentrations were 64% and 35% above baseline, respectively) during the first 24 hours. Mean lipoprotein lipid and apolipoprotein levels were not different during the 2 collecting periods, however. Serum lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, was also unchanged. The fecal excretion of cholesterol (neutral sterols and bile acids) increased in all subjects (mean increase, +39% and +30%, respectively), corresponding to the removal of approximately 500 mg/d excess cholesterol after infusion. Control infusions with only liposomes in 2 of the patients did not influence lipoprotein pattern or cholesterol excretion.
Infusion of proapoA-I liposomes in humans promotes net cholesterol excretion from the body, implying a stimulation of reverse cholesterol transport. This mechanism may prove useful in the treatment of atherosclerosis.
Transition state for radical induced internucleotide hydrogen abstraction, leading to DNA strand break or base release.
DNA damages caused by a 5-hydroxy-5,6-dihydrothymine-6-yl radical (5-OHT-6yl) ...abstracting a C2′ hydrogen from a neighboring sugar (inter-H abstraction) have been theoretically investigated using hybrid DFT in gas phase and in water solution. The inter-H abstraction was here shown to be comparable in energy (24kcalmol−1) with the intra-H abstraction in which the 5-OHT-6yl abstracts a C2′ hydrogen from its own sugar. The effect of a neutrally or a negatively charged phosphate group was also studied and the results show no significant impact on the activation energy of the hydrogen abstraction whereas base release and strand break reactions are affected.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The aim of this study was to achieve realistic levels of two different types of aerosols commonly abundant in indoor environments in an experimental chamber intended for human exposure studies and ...aerosol characterization. The aerosols chosen were particles from candle lights (in particle number dominated by inorganic water soluble particles) and from ozone–terpene reactions (organic particles). The aerosol generation and characterization system consisted of a controlled air tight stainless steel 22m3 chamber, to which the generation set-ups were connected. No air could enter or leave the chamber except through a conditioning system by which temperature, relative humidity and air exchange rate could be controlled. Candle smoke aerosol was generated from ten candles burning in a 1.33m3 glass and stainless steel chamber. The aerosol was diluted by clean air from the conditioning system before entering the chamber. Terpene vapor was generated by passing pure nitrogen through a glass bottle containing limonene oil. Ozone was generated by a spark discharge using pure O2, and was added to the ventilation air flow downstream the inlet for terpene vapors and upstream the inlet to the chamber. Both aerosols were characterized with respect to number and mass concentrations, size distribution and chemical composition. Particle number concentration in the size range 10–650nm could be varied from <10cm−3 to more than 900,000 cm-3 (for candle smoke) or to more than 30,000cm−3 (for particles formed in a 160ppb terpene/40ppb ozone mixture). Furthermore, the set-ups were evaluated by, for each source, repeating the generation at six three-hour long events. For both aerosols repeatable generations at pre-determined concentration levels, that were stable over time, could be achieved. The results show that realistic concentrations of aerosols from real-world environments could be reproduced in a well-controlled manner and that this set-up could be used both for aerosol characterization and for human exposures.
► Generation setups of candle smoke and terpene–ozone particles are described. ► Aerosol characterization methods ensured realistic aerosols for human exposure. ► Generations at pre-determined concentrations were repeatable and stable over time.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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