Performance comparison of Yb:YAG ceramics and crystal gain material in a large-area, high-energy, high average-power diode-pumped laser.

We compare for the first time the influence of different Yb:YAG gain media on the performance of a large-area, high average-power laser system with an output energy of up to 6 J. Monocrystalline slabs grown by a new technique without central growth defect are compared with ceramics. Small signal gain, maximum output energy and thermal lensing are compared for ceramic slabs with co-sintered amplified spontaneous emission (ASE) absorber cladding, monocrystalline slab with and without optically bonded ASE absorber cladding, and surface structured monocrystalline slabs. We show that these large monocrystals with optically bonded absorber cladding have similar performance to cladded ceramics, so far the only material for high-energy Yb:YAG lasers.

Concentrations of hormones, pharmaceuticals and other micropollutants in groundwater affected by septic systems in New England and New York.

Septic-system discharges can be an important source of micropollutants (including pharmaceuticals and endocrine active compounds) to adjacent groundwater and surface water systems. Groundwater samples were collected from well networks tapping glacial till in New England (NE) and sandy surficial aquifer New York (NY) during one sampling round in 2011. The NE network assesses the effect of a single large septic system that receives discharge from an extended health care facility for the elderly. The NY network assesses the effect of many small septic systems used seasonally on a densely populated portion of Fire Island. The data collected from these two networks indicate that hydrogeologic and demographic factors affect micropollutant concentrations in these systems. The highest micropollutant concentrations from the NE network were present in samples collected from below the leach beds and in a well downgradient of the leach beds. Total concentrations for personal care/domestic use compounds, pharmaceutical compounds and plasticizer compounds generally ranged from 1 to over 20 µg/L in the NE network samples. High tris(2-butoxyethyl phosphate) plasticizer concentrations in wells beneath and downgradient of the leach beds (>20 µg/L) may reflect the presence of this compound in cleaning agents at the extended health-care facility. The highest micropollutant concentrations for the NY network were present in the shoreline wells and reflect groundwater that is most affected by septic system discharges. One of the shoreline wells had personal care/domestic use, pharmaceutical, and plasticizer concentrations ranging from 0.4 to 5.7 µg/L. Estradiol equivalency quotient concentrations were also highest in a shoreline well sample (3.1 ng/L). Most micropollutant concentrations increase with increasing specific conductance and total nitrogen concentrations for shoreline well samples. These findings suggest that septic systems serving institutional settings and densely populated areas in coastal settings may be locally important sources of micropollutants to adjacent aquifer and marine systems.

High-energy, ceramic-disk Yb:LuAG laser amplifier.

We report the first short-pulse amplification results to several hundred millijoule energies in ceramic Yb:LuAG. We have demonstrated ns-pulse output from a diode-pumped Yb:LuAG amplifier at a maximum energy of 580 mJ and a peak optical-to-optical efficiency of 28% at 550 mJ. In cavity dumped operation of a nanosecond oscillator we obtained 1 mJ at up to 100 Hz repetition rate. A gain bandwidth of 5.4 nm was achieved at room temperature by measuring the small-signal single-pass gain. Furthermore, we compared our results with Yb:YAG within the same amplifier system.

Combined sewer overflows: an environmental source of hormones and wastewater micropollutants.

Data were collected at a wastewater treatment plant (WWTP) in Burlington, Vermont, USA, (serving 30,000 people) to assess the relative contribution of CSO (combined sewer overflow) bypass flows and treated wastewater effluent to the load of steroid hormones and other wastewater micropollutants (WMPs) from a WWTP to a lake. Flow-weighted composite samples were collected over a 13 month period at this WWTP from CSO bypass flows or plant influent flows (n = 28) and treated effluent discharges (n = 22). Although CSO discharges represent 10% of the total annual water discharge (CSO plus treated plant effluent discharges) from the WWTP, CSO discharges contribute 40-90% of the annual load for hormones and WMPs with high (>90%) wastewater treatment removal efficiency. By contrast, compounds with low removal efficiencies (<90%) have less than 10% of annual load contributed by CSO discharges. Concentrations of estrogens, androgens, and WMPs generally are 10 times higher in CSO discharges compared to treated wastewater discharges. Compound concentrations in samples of CSO discharges generally decrease with increasing flow because of wastewater dilution by rainfall runoff. By contrast, concentrations of hormones and many WMPs in samples from treated discharges can increase with increasing flow due to decreasing removal efficiency.

Osteoporosis in the community: Sensitivity of self-reported estimates and medication use of those diagnosed with the condition.

OBJECTIVES: To assess the sensitivity and specificity of self-reported osteoporosis compared with dual energy X-ray absorptiometry (DXA) defined osteoporosis, and to describe medication use among participants with the condition. METHODS: Data were obtained from a population-based longitudinal study and assessed for the prevalence of osteoporosis, falls, fractures and medication use. DXA scans were also undertaken. RESULTS: Overall 3.8% (95% confidence interval (CI) 3.2 to 4.5) of respondents and 8.8% (95% CI 7.5 to 10.3) of those aged ≥ 50 years reported that they had been diagnosed with osteoporosis by a doctor. The sensitivity (those self-reporting osteoporosis and having low bone mineral density (BMD) on DXA) was low (22.7%), although the specificity was high (94.4%). Only 16.1% of those aged ≥ 50 years and with DXA-defined osteoporosis were taking bisphosphonates. CONCLUSIONS: The sensitivity of self-reporting to identify osteoporosis is low. Anti-osteoporotic medications are an important part of osteoporosis treatment but opportunities to use appropriate medications were missed and inappropriate medications were used.

The effect of temperature and humidity on the permeability of film dressings.

The moisture vapour permeability of a dressing can make an important contribution to its overall fluid handling capacity. Despite the fact that this parameter is often quoted in scientific literature and manufacturers' promotional material, it is a concept that is not generally well understood. In particular, the effect of changing environmental conditions upon experimentally determined permeability values for particular dressings is rarely acknowledged. The present study was undertaken to derive and validate a method that could be used to predict the permeability of a self-adhesive semipermeable film dressing under specific conditions of temperature and humidity using a single set of data generated in the laboratory. A calculator that facilitates this process is also described.

Diffraction contrast STEM of dislocations: imaging and simulations.

The application of scanning transmission electron microscopy (STEM) to crystalline defect analysis has been extended to dislocations. The present contribution highlights the use of STEM on two oppositely signed sets of near-screw dislocations in hcp α-Ti with 6wt% Al in solid solution. In addition to common systematic row diffraction conditions, other configurations such as zone axis and 3g imaging are explored, and appear to be very useful not only for defect analysis, but for general defect observation. It is demonstrated that conventional TEM rules for diffraction contrast such as g·b and g·R are applicable in STEM. Experimental and computational micrographs of dislocations imaged in the aforementioned modes are presented.

Optimising the efficiency of pulsed diode pumped Yb:YAG laser amplifiers for ns pulse generation.

We present a numerical model of a pulsed, diode-pumped Yb:YAG laser amplifier for the generation of high energy ns-pulses. This model is used to explore how optical-to-optical efficiency depends on factors such as pump duration, pump spectrum, pump intensity, doping concentration, and operating temperature. We put special emphasis on finding ways to achieve high efficiency within the practical limitations imposed by real-world laser systems, such as limited pump brightness and limited damage fluence. We show that a particularly advantageous way of improving efficiency within those constraints is operation at cryogenic temperature. Based on the numerical findings we present a concept for a scalable amplifier based on an end-pumped, cryogenic, gas-cooled multi-slab architecture.

Benchmarking of electro-optic monitors for femtosecond electron bunches.

The longitudinal profiles of ultrashort relativistic electron bunches at the soft x-ray free-electron laser FLASH have been investigated using two single-shot detection schemes: an electro-optic (EO) detector measuring the Coulomb field of the bunch and a radio-frequency structure transforming the charge distribution into a transverse streak. A comparison permits an absolute calibration of the EO technique. EO signals as short as 60 fs (rms) have been observed, which is a new record in the EO detection of single electron bunches and close to the limit given by the EO material properties.

In vitro metabolism of a triclyclic alkaloid (M445526) in human liver microsomes and hepatocytes.

The in vitro metabolism of M445,526 (ZD6,126 phenol) was investigated by incubating [(14)C]-M445,526 at a concentration of 10 microg ml(-1) with human hepatic microsomes (4 mg ml(-1)) or human hepatocytes (2 x 10(6) cells ml(-1)) for up to 180 min. Following incubation with microsomes and hepatocytes, up to 78% and 40% of [(14)C]-M445,526 was metabolized after 180 and 120 min, respectively. High-performance liquid chromatography (HPLC) with radiochemical detection confirmed extensive metabolism of [(14)C]-M445,526 by microsomes and hepatocytes. Mass spectrometry and (1)H-NMR spectroscopy enabled structural identification of up to eight metabolites. Human liver microsomes formed one major (O-desmethyl) and three minor (a further O-desmethyl and two different hydroxylated) phase I metabolites. Human hepatocytes produced one major metabolite, a sulphate conjugate of the major O-desmethyl metabolite formed by microsomes. Four minor metabolites were also formed, primarily by O-demethylation with subsequent glucuronidation. Taken collectively, [(14)C]-M445,526 underwent extensive in vitro metabolism by human liver fractions. These data were confirmed by subsequent human in vivo studies.

The increasing prevalence of diabetes in South Australia: the relationship with population ageing and obesity.

OBJECTIVES: To use representative population surveillance data to monitor and project changes in the prevalence of diabetes for different age and body mass index (BMI) groups. STUDY DESIGN: Representative, annual, face-to-face South Australian Health Omnibus Surveys, 1991-2003 (n=3000 per year). METHODS: Trends in self-reported diabetes prevalence by age group and BMI were examined. Separate projections were made on the basis of predicted changes in population demography and diabetes prevalence. RESULTS: The age-sex standardized absolute prevalence of self-reported diabetes among people aged 15 years and over increased from 3.5% in 1991 to 6.7% in 2003. If this current trend continues, the prevalence is expected to increase to 10.5% by 2016. The prevalence of diabetes was significantly higher among those classified as obese (6.5% in 1991 to 12.2% in 2003) than those with normal BMI. The greatest relative percentage increase in prevalence between 1991 and 2003 (169%) was seen among people aged 15-39 years. Taking both age group and BMI classification into account, the greatest relative percentage increases over this time were seen among those with normal BMI aged 60 years or older (148%), and those who were obese and aged less than 60 years (139%). CONCLUSIONS: The prevalence of diabetes and obesity increased significantly between 1991 and 2003. Population ageing and an increase in diabetes prevalence in the future will further increase the burden of diabetes. Future increases in diabetes prevalence are not inevitable, however, if investments are made in public health prevention programmes, particularly those addressing obesity.

HPLC-NMR with severe column overloading: fast-track metabolite identification in urine and bile samples from rat and dog treated with [14C]-ZD6126.

The subject of this study was the determination of the major urinary and biliary metabolites of [(14)C]-ZD6126 following i.v. administration to female and male bile duct cannulated rats at 10 mg/kg and 20 mg/kg, respectively, and male bile duct cannulated dogs at 6 mg/kg by HPLC-NMR spectroscopy. ZD6126 is a phosphorylated pro-drug, which is rapidly hydrolysed to the active metabolite, ZD6126 phenol. The results presented here demonstrate that [(14)C]-ZD6126 phenol is subsequently metabolised extensively by male dogs and both, male and female rats. Recovery of the dose in bile and urine was determined utilising the radiolabel, revealing biliary excretion as the major route of excretion (93%) in dog, with the majority of the radioactivity recovered in both biofluids in the first 6 h. In the rat, greater than 92% recovery was obtained within the first 24 h. The major route of excretion was via the bile 51-93% within the first 12 h. The administered phosphorylated pro-drug was not observed in any of the excreta samples. Metabolite profiles of bile and urine samples were determined by high performance liquid chromatography with radiochemical detection (HPLC-RAD), which revealed a number of radiolabelled components in each of the biofluids. The individual metabolites were subsequently identified by HPLC-NMR spectroscopy and HPLC-MS. In the male dog, the major component in urine and bile was the [(14)C]-ZD6126 phenol glucuronide, which accounted for 3% and 77% of the dose, respectively. [(14)C]-ZD6126 phenol was observed in urine at 1% of dose, but was not observed in bile. A sulphate conjugate of demethylated [(14)C]-ZD6126 phenol was identified in bile by HPLC-NMR and confirmed by HPLC-MS. In the rat, the bile contained two major radiolabelled components. One was identified as the [(14)C]-ZD6126 phenol glucuronide, the other as a glucuronide conjugate of demethylated [(14)C]-ZD6126 phenol. However, a marked difference in the proportions of these two components was observed between male and female rats, either due to a sex difference in metabolism or a difference in dose level. The glucuronide conjugate of the demethylated [(14)C]-ZD6126 phenol was present at higher concentration in the bile of male rats (4-34%), while the phenol glucuronide was present at higher concentration in the bile of female rats (8-70%) over a 0-6 h collection period. A third component was only observed in the bile samples (0-6 h and 6-12 h) of male rats. This was identified as being the same sulphate conjugate of demethylated [(14)C]-ZD6126 phenol as the one observed in dog bile. The rat urines contained two main metabolites in greatly varying concentrations, namely the demethylated [(14)C]-ZD6126 phenol glucuronide and the glucuronide of [(14)C]-ZD6126 phenol. Again, the differences in relative amounts between male and female rats were observed, the major metabolite in the urines from male rats being the demethylated [(14)C]-ZD6126 phenol (0-17% in 0-24 h), whilst the phenol glucuronide, accounting for 0.5-50% of the dose over 0-24 h, was the major metabolite in females. Methanolic extracts of the pooled biofluid samples were submitted for HPLC-NMR for the quick identification of the major metabolites. Following a single injection of the equivalent of 6-28 ml of the biofluids directly onto the HPLC-column with minimal sample preparation, the metabolites could be largely successfully isolated. Despite severe column overloading, the major metabolites of [(14)C]-ZD6126 could be positively identified, and the results are presented in this paper.

Spin relaxation by transient monopolar and bipolar optical orientation.

We have used two-color time-resolved spectroscopy to measure the relaxation of electron spin polarizations in a bulk semiconductor. The circularly polarized pump beam induces a polarization either by direct excitation from the valence band, or by free-carrier (Drude) absorption when tuned to an energy below the band gap. We find that the spin relaxation time, measured with picosecond time resolution by resonant induced Faraday rotation in both cases, increases in the presence of photogenerated holes. In the case of the material chosen, n-InSb, the increase was from 14 to 38 ps.

Stimulated terahertz stokes emission of silicon crystals doped with antimony donors.

Stimulated Stokes emission has been observed from silicon crystals doped by antimony donors when optically excited by radiation from a tunable infrared free electron laser. The photon energy of the emission is equal to the pump photon energy reduced by the energy of the intervalley transverse acoustic (TA) g phonon in silicon (approximately 2.92 THz). The emission frequency covers the range of 4.6-5.8 THz. The laser process occurs due to a resonant coupling of the 1s(E) and 1s(A1) donor states (separation approximately 2.97 THz) via the g-TA phonon, which conserves momentum and energy within a single impurity center.

Osteoporosis screening in people with airways disease.

We tested associations between risk factors and bone mineral density in airways disease subjects, and developed a clinical screening tool to identify people who could benefit from bone mineral density testing. Subjects were recruited through hospital outpatients and pharmacies (Newcastle, n = 172). With survey refinement, we then tested a revised tool in a second sample (Adelaide, n = 317). Study factors included oral/inhaled corticosteroid use, asthma severity, respiratory admissions, physical activity, percent predicted forced expiratory volume in one second (FEV1), body mass index, and smoking history. Outcomes were bone mineral density of lumbar vertebra (L2-4) and total (or neck of) femur. Analysis was logistic regression with generation of a simple screening algorithm based upon coefficients. Scoring algorithm risk factors for T-score of < - 2.0: age > or = 68 = 10 points, bone mineral density < 20 = 25, weight < 60 kg = 20, 60-69 kg = 10, > or = 80 cigarette pack years = 15, low-level leisure activity = 5, area under receiver operator curve 0.83. For a cut-off score of 10, sensitivity was 91.2%, specificity 53.9%, positive and negative predictive values 52.3 and 91.7%, and 67.2% were correctly classified. In conclusions, our model has acceptable sensitivity, although limited specificity. Use of this tool may reduce unnecessary referrals for bone mineral density measurement.

Cytochrome P450-dependent metabolism of gefitinib.

The in vitro metabolism of [(14)C]-gefitinib (1-3 microM) was investigated using human liver microsomes and a range of expressed human cytochrome P450 enzymes, with particular focus on the formation of O-desmethyl-gefitinib (M523595), the major metabolite observed in human plasma. High-performance liquid chromatography with ultraviolet light, radiochemical and mass spectral analysis, together with the availability of authentic standards, enabled quantification and structural identification of metabolites. On incubation with pooled human liver microsomes, [(14)C]-gefitinib underwent rapid and extensive metabolism to a number of metabolites, although M523595 was only a minor microsomal product. Formation of most metabolites was markedly decreased by ketoconazole, but M523595 production was inhibited only by quinidine. Gefitinib was metabolized extensively by expressed CYP3A4, producing a similar range of metabolites to liver microsomes, but M523595 was not formed. CYP1A2, 2C9 and 2C19 produced no measurable metabolism of gefitinib, while CYP3A5 produced a range of metabolites similar to CYP3A4, but to a much lower degree. In contrast, CYP2D6 catalysed rapid and extensive metabolism of gefitinib to M523595. While formation of M523595 was CYP2D6 mediated, the overall metabolism of gefitinib was dependent primarily on CYP3A4, and this was not obviously diminished in liver microsomes from CYP2D6 poor metabolizers.

Randomized controlled trial of alendronate in airways disease and low bone mineral density.

BACKGROUND: Patients with airways disease have been demonstrated to be at risk of osteoporosis, and this is likely to be multifactorial. Our aim was to identify patients with low bone mineral density (BMD) using a screening program, and then evaluate the benefit of daily alendronate. METHOD: Subjects with hip or lumbar spine baseline T-scores < - 2.5, or Z-score < - 1.0 commenced on alendronate/calcium (10 mg/600 mg day) or placebo/calcium, in a double blind randomized controlled trial. BMD by dual emission X-ray absorptiometry (lumbar vertebrae 2-4, neck of femur, total femur) was repeated after 12 months, with adverse events recorded. RESULTS: 145 subjects (74 male, 71 female, mean age 67, median FEV1 1.0 litres = 43% of predicted) were enrolled; 66 alendronate/calcium, 79 placebo/calcium with 24 and 26 withdrawals, respectively. Per protocol but not intention to treat analysis of covariance demonstrated statistically significant improvements in T and Z scores for lumbar spine bone mineral density (P = 0.035, P = 0.040), with no improvement demonstrated at the hip. CONCLUSIONS: Improvement in bone mineral density has been demonstrated at the lumbar spine, but not hip, by per protocol analysis, with daily alendronate, at 12 months.

In vitro metabolism of gefitinib in human liver microsomes.

The in vitro metabolism of gefitinib was investigated by incubating [14C]-gefitinib, as well as M537194, M387783 and M523595 (the main metabolites of gefitinib observed in man), at a concentration of 100 microM with human liver microsomes (4 mg ml(-1)) for 120 min. These relatively high substrate and microsomal protein concentrations were used in an effort to generate sufficient quantities of metabolites for identification. HPLC with ultraviolet light, radiochemical and mass spectral analysis, together with the availability of authentic standards, enabled quantification and structural identification of a large number of metabolites. Although 16 metabolites were identified, metabolism was restricted to three regions of the molecule. The major pathway involved morpholine ring-opening and step-wise removal of the morpholine ring and propoxy side chain. O-demethylation of the quinazoline methoxy group was a quantitatively less important pathway, in contrast to the clinical situation, where O-desmethyl gefitinib (M523595) is the predominant plasma metabolite. The third metabolic route, oxidative defluorination, was only a minor route of metabolism. Some metabolites were formed by a combination of these processes, but no metabolism was observed in other parts of the molecule. Incubation of gefitinib produced ten identified metabolites, but the use of the three main in vivo metabolites as additional substrates enabled a more comprehensive metabolic pathway to be constructed and this has been valuable in supporting the more limited data available from the human in vivo study.

PLD1b in IIC9 fibroblasts is selectively activated in the nucleus and not in the Golgi apparatus.

Mitogen-induced activation of a nuclear-acting PC-phospholipase D (PLD) is mediated, at least in part, by the translocation of RhoA to the nucleus. A remaining question is whether PLD in all subcellular compartments is regulated in the same manner. To address this question, we identified PLD in another subcellular compartment and determined whether its activity was influenced by alpha-thrombin in a RhoA-dependent manner. The data in this manuscript show that nuclear PLD is selectively regulated. alpha-Thrombin stimulates an increase in PLD activity in IIC9 fibroblast nuclei while Golgi PLD activity is unaffected. We cloned PLD1 from IIC9s (hamPLD1b) to show that it is present in both nuclei and Golgi. Interestingly, only nuclear PLD1 is modulated by alpha-thrombin, demonstrating that this activity is selectively regulated. These data provide support for the physiological importance of agonist-induced nuclear signalling enzymes.