On the rate of crack extension due to transverse shear fatique loading

During the period of crack initiation, extremely small microcracks form. The fatigue life of any structure may be divided into three distinct subdivisions: crack initiation, crack growth, and total failure. The principal objective of this thesis is the design of a simple machine that may be used in the study of growth phenomena of a small crack in an aluminum plate due to a transverse shear fatigue load

Cost-effectiveness of pioglitazone in type 2 diabetes patients with a history of macrovascular disease: a German perspective

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

UV and blue light regulation of transcription of the chalcone synthase gene in Arabidopsis

In order to identify light responsive cis-acting DNA sequence elements of the Arabidopsis thaliana chalcone synthase gene (AtCHS) concerned with induction by UV-B and UV-A/blue light, we developed a UV/blue light inducible transient expression system. This system involved transfection of chimaeric AtCHS promoter constructs into Arabidopsis cell culture protoplasts. The reporter enzyme beta-glucuronidase (GUS) was used to monitor light responsive promoter activity. Development of this system involved defining and optimising procedures for preparing protoplasts from the Arabidopsis cell culture, transfection of chimaeric AtCHS promoter constructs into the protoplasts and incubation under defined illumination conditions. An efficient homologous protoplasts transient expression system was developed which subsequently enabled us to undertake functional analysis of the AtCHS promoter. Application of the transient expression system allowed us to define the light responsive cis-acting elements concerned with the transcriptional activation of AtCHS. This analysis showed that a 1972 bp promoter conferred UV-B and UV-A/blue light induction of GUS activity. Deletion of the promoter to 164 bp resulted in reduced promoter strength but retention of responsiveness to UV-B and UV-A/blue light. Further deletion abolished transcriptional activity. The 164 bp promoter contains sequences closely resembling the light-responsive unit (LRUPcCHS) of the Petroselinum crispum CHS promoter. This Arabidopsis CHS promoter region, designated LRUPcCHS, was sufficient to confer UV-B and UV-A/blue light responsiveness to a heterologous core promoter. Mutation of sequences in corresponding to the ACGT element and the MYB recognition element of LRUPcCHS resulted in inactivation of 164 bp and 335 bp promoter deletions. However, the mutant 668 bp promoter retained residual UV-B and UV-A/blue light-induced expression, indicating the presence of additional functional sequences upstream of -335. Mutation of a single G-box-like sequence around -442 had no effect on light responsiveness, indicating that it does not function in the light regulation of this promoter. Furthermore, in this analysis no difference in responsiveness to UV-B and UV-A/blue light was observed with any promoter variant tested. This suggests that the UV-B and the UV-A/blue phototransduction pathways regulate transcription factors which interact with common promoter elements. These results are discussed. We employed several different approaches to investigate the role of cryptochromes in the regulation of AtCHS promoter activity. Gain of function transient expression analysis suggests that CRY1 is the primary photoreceptor mediating UV- A/blue light induction of promoter activity. In addition, northern analysis using various cryptochrome mutant lines, including a cry1/cry2 double mutant, supports this hypothesis and, furthermore, suggests that (an)other photoreceptor(s) able to respond to UV-A/blue light, exist in Arabidopsis. Possible reasons for these observations are discussed. We used the transient expression system to investigate the role of sugar regulation in the control of AtCHS promoter activity in Arabidopsis protoplasts. This revealed that sucrose, glucose or fructose was required to stimulate AtCHS promoter activity. Furthermore, studies using glucose analogues were performed which suggest that the initial signal for sugar stimulation of AtCHS promoter activity is consistent with signalling by hexokinase phosphorylation of hexose sugars. Evidence for this hypothesis is discussed. (Abstract shortened by ProQuest.)

Cost-Effectiveness of Early versus Late Cinacalcet Treatment in Addition to Standard Care for Secondary Renal Hyperparathyroidism in the USA

AbstractObjectivesThe objective of this research was to estimate lifetime cost-effectiveness of treating patients with cinacalcet early (when parathyroid hormone [PTH] levels are in the range of 300–500 pg/ml) versus delaying treatment with cinacalcet (cinacalcet initiated when PTH levels are >800 pg/ml) in patients with secondary hyperparathyroidism (SHPT) in the US setting.MethodsA Markov model was developed to simulate the effects of early versus delayed use of cinacalcet (plus standard of care). Four different PTH ranges (≤300 pg/ml; 301–500 pg/ml; 501–800 pg/ml; >800 pg/ml) were used to represent four different health states within the Markov model. Associated with each Markov state (PTH range) were varying risks of major SHPT complications, including cardiovascular disease (CVD), fracture (Fx), and parathyroidectomy (PTx). Baseline cohort characteristics and risks of CVD, Fx, and PTx by PTH category were derived from a large US renal database and published sources. Costs were estimated from the US Renal Data System database and reported in 2006 US Dollars ($). Clinical and economic outcomes were discounted at 3.0$17,275 per QALY gained.ConclusionsEarly treatment with cinacalcet was associated with improvements in QALYs and would represent good value for money compared to delaying treatment with cinacalcet

Cost-effectiveness of irbesartan in diabetic nephropathy: a systematic review of published studies

Background. To review published studies on the cost-effectiveness of the use of irbesartan for treatment of advance overt nephropathy in patients with type 2 diabetes and hypertension. Methods. Articles were identified based on a search of the PubMed databases using the keywords ‘irbesartan', ‘ESRD', ‘cost-effectiveness', ‘nephropathy' and ‘costs', and by personal communication with the authors. Only studies published in the last 10 years were included. All costs data from the cost-effectiveness studies were inflated to 2003 Euros using published governmental conversion tables. Results. Seven published studies were identified, spanning the following country settings: the US, Belgium and France, Germany, Hungary, Italy, Spain, and the UK. In each, the same pharmacoeconomic model was adapted using country-specific data to project and evaluate the clinical and cost outcomes of the treatment arms of the Irbesartan in Diabetic Nephropathy Trial (IDNT) (irbesartan, amlodipine or standard blood pressure control). Mean time to onset of ESRD was 8.23 years for irbesartan, 6.82 years for amlodipine and 6.88 years for the control (values were the same for Belgium, France, Germany, Hungary, Italy and Spain as transition probabilities for progression to ESRD were all derived from the IDNT). Mean cumulative incidence of ESRD was 36% with irbesartan, 49% with amlodipine and 45% with control treatment. Treatment with irbesartan was projected to improve life expectancy compared to both amlodipine and control in all seven published studies. Analysis of total lifetime costs showed that irbesartan treatment was cost saving compared to the other two treatment regimens, due to the associated reduction in ESRD cases. Cost savings with irbesartan became evident very early; after 2-3 years of treatment in most settings. Conclusions. Modelling studies based on the IDNT published to date suggest that irbesartan treatment in patients with type 2 diabetes, hypertension and advanced nephropathy is both life- and cost-saving compared to amlodipine or contro

Hybrid Ion-Detector/Data-Acquisition System for a TOF-MS

A modified ion-detector/data-acquisition system has been devised to increase the dynamic range of a time-of-flight mass spectrometer (TOF-MS) that, previously, included a microchannel-plate detector and a data-acquisition system based on counting pulses and time-tagging them by use of a time-to-digital converter (TDC). The dynamic range of the TOF-MS was limited by saturation of the microchannel plate detector, which can handle no more than a few million counts per second. The modified system includes (1) a combined microchannel plate/discrete ion multiplier and (2) a hybrid data-acquisition system that simultaneously performs analog current or voltage measurements and multianode single-ion-pulse-counting time-of-flight measurements to extend the dynamic range of a TDC into the regime in which a mass peak comprises multiple ions arriving simultaneously at the detector. The multianode data are used to determine, in real time, whether the detector is saturated. When saturation is detected, the data-acquisition system selectively enables circuitry that simultaneously determines the ion-peak intensity by measuring the time profile of the analog current or voltage detector-output signal

Herbivores at the Highest Risk of Extinction Among Mammals, Birds, and Reptiles

As a result of their extensive home ranges and slow population growth rates, predators have often been perceived to suffer higher risks of extinction than other trophic groups. Our study challenges this extinction-risk paradigm by quantitatively comparing patterns of extinction risk across different trophic groups of mammals, birds, and reptiles. We found that trophic level and body size were significant factors that influenced extinction risk in all taxa. At multiple spatial and temporal scales, herbivores, especially herbivorous reptiles and large-bodied herbivores, consistently have the highest proportions of threatened species. This observed elevated extinction risk for herbivores is ecologically consequential, given the important roles that herbivores are known to play in controlling ecosystem function