Aims/hypothesis The 825C>T polymorphism in the gene encoding the G protein β3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation. This polymorphism is also ...repeatedly associated with an increased risk of hypertension and has been studied in relation to obesity with divergent results. Only a few association studies have investigated whether this polymorphism is related to type 2 diabetes or the metabolic syndrome. We estimated the impact of the GNB3 825C>T polymorphism in relatively large-scale association studies of common phenotypes of the metabolic syndrome. Materials and methods The GNB3 825C>T polymorphism was genotyped in 7,518 white Danish subjects using mass spectrometry analysis of PCR products. Case-control studies were undertaken for obesity, hypertension, type 2 diabetes and the metabolic syndrome, and a meta-analysis including data from the present study and previous studies of hypertension was performed. Quantitative trait studies of metabolic variables were carried out in 4,387 glucose-tolerant subjects. Results We observed minor differences in 825C>T genotype distributions for type 2 diabetes (CC/CT/TT 49/41/10% (control) vs 46/46/9% (cases), respectively, p=0.007); however, after correction for multiple testing, these were not statistically significant. No association was found with hypertension, obesity or the metabolic syndrome. Curiously, the T allele was associated with nominally lower systolic and diastolic blood pressure levels--a finding in contrast with most previous studies-but not with other metabolic variables. Meta-analysis demonstrated a high degree of heterogeneity between study populations of different ethnic origin. Although there was a tendency towards an increased risk of hypertension among 825T allele carriers, this was not statistically significant. Conclusions/interpretation The present study suggests no major involvement of the GNB3 825C>T polymorphism in components of the metabolic syndrome.
The insulin-like growth factor (IGF) system plays an important role in regulating ovarian follicular development and steroidogenesis. IGF binding proteins (IGFBP) mostly inhibit IGF actions, and ...IGFBP proteolysis is a major mechanism for regulating IGF bioavailability. Pregnancy-associated plasma protein-A (PAPPA) is a secreted metalloprotease responsible for cleavage of IGFBP4 in the ovary. The aim of this study was to investigate whether PAPPA plays a role in regulating ovarian functions and female fertility by comparing the reproductive phenotype of wild-type (WT) mice with mice heterozygous or homozygous for a targeted Pappa gene deletion (heterozygous and PAPP-A knockout KO mice, respectively). When mated with WT males, PAPP-A KO females demonstrated an overall reduction in average litter size. PAPP-A KO mice had a reduced number of ovulated oocytes, lower serum estradiol levels following equine chorionic gonadotropin administration, lower serum progesterone levels after human chorionic gonadotropin injection, and reduced expression of ovarian steroidogenic enzyme genes, compared to WT controls. In PAPP-A KO mice, inhibitory IGFBP2, IGFBP3, and IGFBP4 ovarian gene expression was reduced postgonadotropin stimulation, suggesting some compensation within the ovarian IGF system. Expression levels of follicle-stimulating hormone receptor, luteinizing hormone receptor, and genes required for cumulus expansion were not affected. Analysis of preovulatory follicular fluid showed complete loss of IGFBP4 proteolytic activity in PAPP-A KO mice, demonstrating no compensation for loss of PAPPA proteolytic activity by other IGFBP proteases in vivo in the mouse ovary. Taken together, these data demonstrate an important role of PAPPA in modulating ovarian function and female fertility by control of the bioavailability of ovarian IGF.
The ESHO protocol 3-85 is a multicentre randomized trial investigating the value of hyperthermia as an adjuvant to radiotherapy in treatment of malignant melanoma. A total of 134 metastatic of ...recurrent malignant melanoma lesions in 70 patients were randomized to receive radiotherapy alone (3 fractions in 8 days) or each fraction followed by hyperthermia (aimed for 43°C for 60 min). Radiation was given with high voltage photons or electrons. Tumours were stratified according to institution and size (above or below 4 cm) and randomly assigned to a total radiation dose of either 24 or 27 Gy to be given with or without hyperthermia. The endpoint was persistent complete response in the treated area. A number of 128 tumours in 68 patients were evaluable, with an observation time between 3 and 72 months. Sixty-five tumours were randomized to radiation alone and 63 to radiation + heat. Sixty received 24 Gy and 68 tumours received 27 Gy, respectively. Size was ≤4 cm in 81 and >4 cm in 47 tumours. Overall the 2-year actuarial local tumour control was 37%. Univariate analysis showed prognostic influence of hyperthermia (rad alone 28% vs. rad + heat 46%, p = 0.008) and radiation dose (24 Gy 25% vs. 27 Gy 56%, p = 0.02), but not of tumour size (small 42% vs. large 29%, p = 0.21). A Cox multivariate regression analysis showed the most important prognostic parameters to be: hyperthermia (odds ratio: 1.73 (1.07-2.78), p = 0.02), tumour size (odds ratio: 0.91 (0.85-0.99), p = 0.05) and radiation dose (odds ratio: 1.17 (1.01-1.36), p = 0.05). Analysis of the heating quality showed a significant relationship between the extent of heating and local tumour response. Addition of heat did not significantly increase the acute or late radiation reactions. The overall 5-year survival rate of the patients was 19%, but 38% in patients if all known disease was controlled, compared to 8% in the patients with persistent active disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The proform of eosinophil major basic protein (ProMBP) exists in serum from pregnant women complexed with a variable fraction of angiotensinogen (Ang). A subfraction further binds complement C3dg in ...a 2:2:2 complex. The function, physiology, and clinical importance of ProMBP complexes are unknown, and the specific quantification of these complexes has not been possible.
We developed an ELISA for the ProMBP/Ang complexes, using a monoclonal antibody against ProMBP for capture and a chicken anti-human Ang antiserum for detection. Calibrators were standardized with WHO IRP 78/610 for pregnancy proteins in the assay range 0.95-15.6 mIU/L.
The concentrations of ProMBP/Ang complexes in serum of nonpregnant blood donors (n = 79) were log-normally distributed with a central 95th interval of 985-3655 mIU/L. In pregnancy, mean serum concentrations were increased from week 7, and the concentrations reached term concentrations in week 18. ProMBP/Ang complexes eluted in gel filtration as a broad peak with a molecular mass of approximately 230 kDa. The concentration of ProMBP/Ang/C3dg increased during blood coagulation, suggesting that the ProMBP/Ang/C3dg complex may be a marker of complement activation.
ProMBP/Ang complexes are present in serum from nonpregnant persons as well as pregnant women, and the direct assays described here will make it possible to study the biochemistry and the clinical significance of different ProMBP complexes in pathological conditions and pregnancy.
The tundra is warming more rapidly than any other biome on Earth, and the potential ramifications are far-reaching because of global feedback effects between vegetation and climate. A better ...understanding of how environmental factors shape plant structure and function is crucial for predicting the consequences of environmental change for ecosystem functioning. Here we explore the biome-wide relationships between temperature, moisture and seven key plant functional traits both across space and over three decades of warming at 117 tundra locations. Spatial temperature–trait relationships were generally strong but soil moisture had a marked influence on the strength and direction of these relationships, highlighting the potentially important influence of changes in water availability on future trait shifts in tundra plant communities. Community height increased with warming across all sites over the past three decades, but other traits lagged far behind predicted rates of change. Our findings highlight the challenge of using space-for-time substitution to predict the functional consequences of future warming and suggest that functions that are tied closely to plant height will experience the most rapid change. They also reveal the strength with which environmental factors shape biotic communities at the coldest extremes of the planet and will help to improve projections of functional changes in tundra ecosystems with climate warming.
Adherence with controller medication is a major challenge in asthma management. Thus, a reliable method of measurement is mandatory to assess adherence.
To examine the test-retest reliability on ...adherence with inhaled corticosteroids in adults with asthma using, a self-reported adherence score (Foster score).
Patients with asthma and >1 routine follow-up appointment at a university hospital outpatient clinic reported Foster scores. The objective Medication Possession Ratio (MPR) was calculated based on pharmacy redemption data and physician-prescribed doses of inhaled corticosteroids. The difference between Foster score and MPR at the first and second visit was assessed using a Bland-Altman plot, outcomes reported as limits of agreements and bias. Foster scores from both visits were used to calculate an intraclass correlation coefficient (ICC).
Self-reported adherence with asthma controller medication measured by Foster score was significantly higher than the objective MPR (p < 0.0001). The Bland-Altman plot for MPR and Foster score at the first and second visit showed upper and lower limits of agreement of 83.5 - (-1.6) and 80.9 - (-6.9) and bias was 41.0 and 37.0, respectively. Of the included patients, 93.1% reported identical Foster scores between visits, resulting in an excellent ICC of 0.92. Absolute median difference between Foster scores and MPR at first and second visit was 8.7 percentage points (p = 0.049).
Foster score shows an excellent ICC; however, its poor agreement with objective measures of adherence suggests that clinicians should not rely on Foster scores alone to assess adherence with inhaled corticosteroids in patients with asthma.
Purpose: The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy.
Materials ...and methods: Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis.
Results: From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (
P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (
P=0.06). Tpot showed no trend (
P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (
P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (
P=0.02). In the multivariate analysis of local control, LI lost its significance (
P=0.16).
Conclusions: The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.
Ovarian insulin-like growth factor binding protein-4 (IGFBP-4)
proteolysis is involved in the regulation of follicular development,
but until now the identity of the responsible enzyme was unknown. ...In
this study, we identify the IGFBP-4 protease in human follicular fluid
as pregnancy associated plasma protein-A (PAPP-A) based on distinctive
IGFBP-4 cleavage pattern, the same protease inhibitor profile, specific
inhibition and immunodepletion of IGFBP-4 protease activity with PAPP-4
polyclonal antibodies, and immunorecognition by PAPP-A monoclonal
antibodies in ELISA. Furthermore, PAPP-A levels in
estrogen-dominant and androgen-dominant follicular fluids reflect their
IGFBP-4 proteolytic activity. PAPP-A was also secreted by human
granulosa cells, the reputed source of IGFBP-4 protease activity in
follicular fluid. We have the molecular and biochemical tools to begin
to delineate the regulation and biological function of PAPP-A in
normal and dysregulated follicular development and atresia.
Real life testing of a Hybrid PEM Fuel Cell Bus Folkesson, Anders; Andersson, Christian; Alvfors, Per ...
Journal of power sources,
05/2003, Letnik:
118, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Fuel cells produce low quantities of local emissions, if any, and are therefore one of the most promising alternatives to internal combustion engines as the main power source in future vehicles. It ...is likely that urban buses will be among the first commercial applications for fuel cells in vehicles. This is due to the fact that urban buses are highly visible for the public, they contribute significantly to air pollution in urban areas, they have small limitations in weight and volume and fuelling is handled via a centralised infrastructure.
Results and experiences from real life measurements of energy flows in a Scania Hybrid PEM Fuel Cell Concept Bus are presented in this paper. The tests consist of measurements during several standard duty cycles. The efficiency of the fuel cell system and of the complete vehicle are presented and discussed. The net efficiency of the fuel cell system was approximately 40% and the fuel consumption of the concept bus is between 42 and 48% lower compared to a standard Scania bus. Energy recovery by regenerative braking saves up 28% energy. Bus subsystems such as the pneumatic system for door opening, suspension and brakes, the hydraulic power steering, the 24
V grid, the water pump and the cooling fans consume approximately 7% of the energy in the fuel input or 17% of the net power output from the fuel cell system.
The bus was built by a number of companies in a project partly financed by the European Commission’s Joule programme. The comprehensive testing is partly financed by the Swedish programme “Den Gröna Bilen” (The Green Car). A 50
kW
el fuel cell system is the power source and a high voltage battery pack works as an energy buffer and power booster. The fuel, compressed hydrogen, is stored in two high-pressure stainless steel vessels mounted on the roof of the bus. The bus has a series hybrid electric driveline with wheel hub motors with a maximum power of 100
kW.
Hybrid Fuel Cell Buses have a big potential, but there are still many issues to consider prior to full-scale commercialisation of the technology. These are related to durability, lifetime, costs, vehicle and system optimisation and subsystem design. A very important factor is to implement an automotive design policy in the design and construction of all components, both in the propulsion system as well as in the subsystems.
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