Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747)

OBJECTIVE: To evaluate the cost-effectiveness of adding zoledronic acid or strontium-89 to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC).

PATIENTS AND METHODS: Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2 × 2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs. no Sr89). Costs were estimated from the perspective of the National Health Service in the UK and included expenditures for trial treatments, concomitant medications, and use of related hospital and primary care services. Quality-adjusted life-years (QALYs) were calculated according to patients' responses to the generic EuroQol EQ-5D-3L instrument, which evaluates health status. Results are expressed as incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves.

RESULTS: The per-patient cost for ZA was £12 667, £251 higher than the equivalent cost in the no ZA group. Patients in the ZA group had on average 0.03 QALYs more than their counterparts in no ZA group. The ICER for this comparison was £8 005. Sr89 was associated with a cost of £13 230, £1365 higher than no Sr89, and a gain of 0.08 QALYs compared to no Sr89. The ICER for Sr89 was £16 884. The probabilities of ZA and Sr89 being cost-effective were 0.64 and 0.60, respectively.

CONCLUSIONS: The addition of bone-targeting treatments to standard chemotherapy led to a small improvement in QALYs for a modest increase in cost (or cost-savings). ZA and Sr89 resulted in ICERs below conventional willingness-to-pay per QALY thresholds, suggesting that their addition to chemotherapy may represent a cost-effective use of resources.

Sulfur-tolerant NOx storage traps: an infrared and thermodynamic study of the reactions of alkali and alkaline-earth metal sulfates

The sulfur tolerance of a barium-containing NOx storage/reduction trap was investigated using infrared analysis. It was confirmed that barium carbonate could be replaced by barium sulfate by reaction with low concentrations of sulfur dioxide (50 ppm) in the presence of large concentrations of carbon dioxide (10%) at temperatures up to 700 degreesC. These sulfates could at least be partially removed by switching to hydrogen-rich conditions at elevated temperatures. Thermodynamic calculations were used to evaluate the effects of gas composition and temperature on the various reactions of barium sulfate and carbonate under oxidizing and reducing conditions. These calculations clearly showed that if, under a hydrogen-rich atmosphere, carbon dioxide is included as a reactant and barium carbonate as a product then barium sulfate can be removed by reaction with carbon dioxide at a much lower temperature than is possible by decomposition to barium oxide. It was also found that if hydrogen sulfide was included as a product of decomposition of barium sulfate instead of sulfur dioxide then the temperature of reaction could be significantly lowered. Similar calculations were conducted using a selection of other alkaline-earth and alkali metals. In this case calculations were simulated in a gas mixture containing carbon monoxide, hydrogen and carbon dioxide with partial pressures similar to those encountered in real exhausts during switches to rich conditions. The results indicated that there are metals such as lithium and strontium with less stable sulfates than barium, which may also possess sufficient NOx storage capacity to give sulfur-tolerant NOx traps.

FhCaBP4: A Fasciola hepatica calcium binding protein with EF-hand and dynein light chain domains

In trematodes, there is a family of proteins which combine EF-hand-containing domains with dynein light chain (DLC)-like domains. A member of this family from the liver fluke, Fasciola hepatica-FhCaBP4-has been identified and characterised biochemically. FhCaBP4 has an N-terminal domain containing two imperfect EF-hand sequences and a C-terminal dynein light chain-like domain. Molecular modelling predicted that the two domains are joined by a flexible linker. Native gel electrophoresis demonstrated that FhCaBP4 binds to calcium, manganese, barium and strontium ions, but not to magnesium or zinc ions. The hydrophobic, fluorescent probe 8-anilinonaphthalene-1-sulphonate bound more tightly to FhCaBP4 in the presence of calcium ions. This suggests that the protein undergoes a conformational change on ion binding which increases the number of non-polar residues on the surface. FhCaBP4 was protected from limited proteolysis by the calmodulin antagonist W7, but not by trifluoperazine or praziquantel. Protein-protein cross-linking experiments showed that FhCaBP4 underwent calcium ion-dependent dimerisation. Since DLCs are commonly dimeric, it is likely that FhCaBP4 dimerises through this domain. The molecular model reveals that the calcium ion-binding site is located close to a key sequence in the DLC-like domain, suggesting a plausible mechanism for calcium-dependent dimerisation.

Phase transitions in epitaxial Ba0.5Sr0.5TiO3 thin films

Ba0.5Sr0.5TiO3 (BST) thin-film capacitor structures with various thicknesses, (50-1200 nm) and different strain conditions (on lanthanum strontium cobalt oxide La0.5Sr0.5CoO3 and strontium ruthenate SrRuO3 buffer layers) were made using pulsed laser deposition, and characterized by x-ray diffraction. The out-of-plane lattice parameter was followed as a function of temperature within the 100-300 K temperature interval. The phase sequence (cubic-tetragonal-orthorhombic-rhombohedral) known to exist in the bulk analog is shown to be strongly affected by both the stress conditions imposed by the buffer layer and the thickness of the BST film itself. Thus, no phase transition was found for the in-plane compressed BST films. On the stress-free BST films, on the contrary, more phase transitions were observed. It appeared that the complexity of structural phase transitions increased as the film thickness in this system was reduced.

Osmoregulatory traits of broad-toothed field mouse (Apodemus mystacinus) populations from different habitats

One mechanism for physiological adjustment of small mammals to different habitats and different seasons is by seasonal acclimatization of their osmoregulatory system. We examined the abilities of broad-toothed field mice (Apodemus mystacinus) from different ecosystems ('sub-alpine' and 'Mediterranean') to cope with salinity stress under short day (SD) and long day (W) photoperiod regimes. We compared urine volume, osmolarity, urea and electrolyte (sodium, potassium and chloride) concentrations. Significant differences were noted in the abilities of mice from the two ecosystems to deal with salinity load; in particular sub-alpine mice produced less concentrated urine than Mediterranean mice with SD- sub-alpine mice seeming to produce particularly dilute urine. Urea concentration generally decreased with increasing salinity, whereas sodium and potassium levels increased, however SD- sub-alpine mice behaved differently and appeared not to be able to excrete electrolytes as effectively as the other groups of mice. Differences observed provide an insight into the kinds of variability that are present within populations inhabiting different ecosystems, thus how populations may be able to respond to potential changes in their environment. Physiological data pertaining to adaptation to increased xeric conditions, as modelled by A. mystacinus, provides valuable information as to how other species may cope with potential climatic challenges.

Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels.

Transient receptor potential canonical (TRPC) channels are Ca(2+)-permeable nonselective cation channels implicated in diverse physiological functions, including smooth muscle contractility and synaptic transmission. However, lack of potent selective pharmacological inhibitors for TRPC channels has limited delineation of the roles of these channels in physiological systems. Here we report the identification and characterization of ML204 as a novel, potent, and selective TRPC4 channel inhibitor. A high throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository was performed for inhibitors that blocked intracellular Ca(2+) rise in response to stimulation of mouse TRPC4ß by µ-opioid receptors. ML204 inhibited TRPC4ß-mediated intracellular Ca(2+) rise with an IC(50) value of 0.96 µm and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In whole-cell patch clamp recordings, ML204 blocked TRPC4ß currents activated through either µ-opioid receptor stimulation or intracellular dialysis of guanosine 5'-3-O-(thio)triphosphate (GTP?S), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10-20 µm ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTP?S, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4.

Bone-targeting radiopharmaceuticals including radium-223

ABSTRACT: Bone-seeking radionuclides including samarium-153 ethylene diamine tetramethylene phosphonate and strontium-89 have been used for decades in the palliation of pain from bone metastases especially from prostate cancer. Emerging evidence of improved survival in metastatic castration-resistant prostate cancer (CRPC) with the first-in-class a-radionuclide, radium-223 (Ra) has rekindled interest in the role of bone-seeking radionuclide therapy.We review the literature for randomized controlled trials of bone-seeking radionuclides and explore some of the issues regarding the optimal use of these agents. In particular, we discuss dose, dose rate, radiobiology, and quality of radiation and postulate on potential future directions in particular combination schedules. ß-Emitting, bone-seeking radionuclides have proven ability to control pain in prostate cancer metastatic to bone with pain response rates in the order of 60% to 70% when used as single agents. Most of the published trials were underpowered to detect differences in survival; however, there is evidence of the potential for disease modification when these agents are used in combination with chemotherapy or in multiple cycles.Data from the recent phase III ALSYMPCA trial that compared Ra to placebo in symptomatic CRPC demonstrate a significant improvement in median overall survival of 3.6 months for patients with symptomatic CRPC metastatic to bone treated with 6 cycles of the a-emitting radionuclide Ra compared with placebo. The success of Ra in improving survival in CRPC will lead this agent to become part of the treatment paradigm for this disease, and with such an excellent safety profile, Ra has huge potential in combination strategies as well as for use earlier in the natural history of metastatic prostate cancer.

The variability in nutrient composition of Anaerobic Digestate granules produced from high shear granulation

This study investigates the production of organic fertilizer using Anaerobic Digestate (as a nutrient source) and limestone powder as the raw materials. A two-level factorial experimental design was used to determine the influence of process variables on the nutrient homogeneity within the granules. Increasing the liquid-to-solid ratio during granulation resulted in increased granule nutrient homogeneity. Increasing the processing time and the impeller speed were also found to increase the nutrient homogeneity. In terms of nutrients release into deionized water, the granules effectively released both potassium and phosphate into solution. © 2012 Elsevier Ltd.

Faulty sausage production causing methaemoglobinaemia

A family outbreak of methaemoglobinaemia following ingestion of sausages made using 'saltpetre' is reported. Saltpetre is a generic term for several potassium and sodium based compounds. On this occasion imprecise ordering led to the use of sodium nitrite rather than the usual potassium nitrate, with extremely serious consequences.