The air temperature change effect on water quality in the Kvarken Archipelago area.

The Kvarken Archipelago is Finland's World Heritage site designated by UNESCO. How climate change has affected the Kvaken Archipelago remains unclear. This study was conducted to investigate this issue by analyzing air temperature and water quality in this area. Here we use long-term historical data sets of 61 years from several monitoring stations. Water quality parameters included chlorophyll-a; total phosphorus; total nitrogen; coliform bacteria thermos tolerant; temperature; nitrate as nitrogen; nitrite-nitrate as nitrogen, and Secchi depth and correlations analysis was conducted to identify the most relevant parameters. Based on the correlation analysis of weather data and water quality parameters, air temperature showed a significant correlation with water temperature (Pearson's correlations = 0.89691, P < 0.0001). The air temperature increased in April (R2 (goodness-of-fit) = 0.2109 &P = 0.0009) and July (R2 = 0.1207 &P = 0.0155) which has indirectly increased the chlorophyll-a level (e.g. in June increasing slope = 0.39101, R2 = 0.4685, P < 0.0001) an indicator of phytoplankton growth and abundance in the water systems. The study concludes that there might be indirect effects of the likely increase in air temperature on water quality in the Kvarken Archipelago, in particular causing water temperature and chlorophyll-a concentration to increase at least in some months.

Shape coexistence in the neutron-deficient even-even (182-188)Hg isotopes studied via coulomb excitation.

Coulomb-excitation experiments to study electromagnetic properties of radioactive even-even Hg isotopes were performed with 2.85 MeV/nucleon mercury beams from REX-ISOLDE. Magnitudes and relative signs of the reduced E2 matrix elements that couple the ground state and low-lying excited states in Hg182-188 were extracted. Information on the deformation of the ground and the first excited 0+ states was deduced using the quadrupole sum rules approach. Results show that the ground state is slightly deformed and of oblate nature, while a larger deformation for the excited 0+ state was noted in Hg182,184. The results are compared to beyond mean field and interacting-boson based models and interpreted within a two-state mixing model. Partial agreement with the model calculations was obtained. The presence of two different structures in the light even-mass mercury isotopes that coexist at low excitation energy is firmly established.

Shell-structure and pairing interaction in superheavy nuclei: rotational properties of the z=104 nucleus (256)rf.

The rotational band structure of the Z=104 nucleus (256)Rf has been observed up to a tentative spin of 20ℏ using state-of-the-art γ-ray spectroscopic techniques. This represents the first such measurement in a superheavy nucleus whose stability is entirely derived from the shell-correction energy. The observed rotational properties are compared to those of neighboring nuclei and it is shown that the kinematic and dynamic moments of inertia are sensitive to the underlying single-particle shell structure and the specific location of high-j orbitals. The moments of inertia therefore provide a sensitive test of shell structure and pairing in superheavy nuclei which is essential to ensure the validity of contemporary nuclear models in this mass region. The data obtained show that there is no deformed shell gap at Z=104, which is predicted in a number of current self-consistent mean-field models.

An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis.

BACKGROUND: Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. OBJECTIVES: To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. DATA SOURCES: Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. REVIEW METHODS: Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. RESULTS: Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control - as an indicator of proper blinding to treatment as a proxy for study quality - associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis. Although the EVI analyses suggested substantial expected net benefit from a large, multicentre randomised controlled trial (RCT) evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. LIMITATIONS: As has been identified in previous meta-analyses, there are issues with the methodological quality of the available evidence. CONCLUSIONS: Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research. Our recommendations for future research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Comparison of gamma-ray coincidence and low-background gamma-ray singles spectrometry.

Aerosol samples have been studied under different background conditions using gamma-ray coincidence and low-background gamma-ray singles spectrometric techniques with High-Purity Germanium detectors. Conventional low-background gamma-ray singles counting is a competitive technique when compared to the gamma-gamma coincidence approach in elevated background conditions. However, measurement of gamma-gamma coincidences can clearly make the identification of different nuclides more reliable and efficient than using singles spectrometry alone. The optimum solution would be a low-background counting station capable of both singles and gamma-gamma coincidence spectrometry.

Capecitabine for the treatment of advanced gastric cancer.

This paper presents a summary of the evidence review group (ERG) report into capecitabine for advanced gastric cancer (aGC). Capecitabine is an oral prodrug of 5-fluorouracil (5-FU). The decision problem addressed was the use of capecitabine (X) compared to 5-FU (F), in combination regimens with platinum agents [cisplatin (C) or oxaliplatin (O)] with or without epirubicin (E), in patients with inoperable aGC. Approximately 7000 new cases of gastric cancer are diagnosed in England and Wales every year. Of these, 80% are candidates for palliative chemotherapy and around 2900 receive such treatment. The standard UK practice for patients with aGC who are considered fit enough has consisted of a triplet regimen comprising intravenous 5-FU in combination with a platinum agent (capecitabine or oxaliplatin) and epirubicin. The manufacturer's submission (MS) focused on direct evidence from two phase III non-inferiority randomised controlled trials (RCTs), REAL-2 (Randomized ECF for Advanced and Locally advanced oesophagogastric cancer-2; n = 1002) and ML17032 (n = 316). REAL-2 randomised patients to four regimens (ECF, ECX, EOF and EOX) to compare 5-FU with capecitabine and cisplatin with oxaliplatin, whereas ML17032 compared CX with CF. Efficacy outcomes from these trials were pooled in an individual patient data (IPD) meta-analysis. Both RCTs demonstrated statistically significant non-inferiority of capecitabine on the outcome of overall survival (OS) assessed in the per-protocol population; equivalent results were also demonstrated for progression-free survival (PFS). The IPD meta-analysis found a statistically significant benefit in OS for capecitabine compared with 5-FU [unadjusted hazard ratio (HR): 0.87; 95% confidence interval (CI) 0.77 to 0.98, p = 0.027]. There was no evidence of a poorer safety profile for capecitabine overall, nor of any difference in quality of life (QoL) between the two fluoropyrimidines. The MS included a de novo economic evaluation based on a cost-minimisation analysis (CMA), where the costs of capecitabine-based regimens were compared with their equivalent 5-FU-based regimens in aGC. A time horizon of 5.5 cycles (each lasting for 21 days) was used in the base-case analysis, representing the duration of treatment. The results of the manufacturer's base-case analysis showed that capecitabine regimens are associated with mean net cost savings of 1620 pounds (ECX vs ECF), 1572 pounds (EOX vs EOF) and 4210 pounds (CX vs CF). The manufacturer failed to comment explicitly on the uncertainty around the estimates of efficacy and on the fact that the IPD meta-analysis suggests that capecitabine may actually be more effective on average. Further analyses exploring additional costs incurred by the UK NHS from extending survival duration showed that these are unlikely to have a material effect on conclusions. A full probabilistic analysis was not performed; however, the evidence explored by the MS and ERG is consistent in suggesting that capecitabine has a lower mean cost than 5-FU-based regimens. The submission was considered to contain convincing evidence of the non-inferiority of capecitabine to 5-FU on survival; this evidence was considered to be applicable to UK practice. Although some uncertainty remains, the ERG deemed CMA to be an appropriate framework with which to analyse this decision problem. Overall cost estimates for the CMA were generated appropriately and were robust to uncertainties regarding assumptions and sources. At the time of writing, the guidance document issued by NICE on 28 July 2010 states that capecitabine in combination with a platinum-based regimen is recommended for the first-line treatment of inoperable advanced gastric cancer.

The effect of rf pulse pattern on bremsstrahlung and ion current time evolution of an ECRIS.

Time-resolved helium ion production and bremsstrahlung emission from JYFL 14 GHz ECRIS is presented with different radio frequency pulse lengths. rf on times are varied from 5 to 50 ms and rf off times from 10 to 1000 ms between different measurement sets. It is observed that the plasma breakdown occurs a few milliseconds after launching the rf power into the plasma chamber, and in the beginning of the rf pulses a preglow transient is seen. During this transient the ion beam currents are increased by several factors compared to a steady state situation. By adjusting the rf pulse separation the maximum ion beam currents can be maintained during the so-called preglow regime while the amount of bremsstrahlung radiation is significantly decreased.

Gamma-ray spectroscopy at the limits: first observation of rotational bands in 255Lr.

The rotational band structure of 255Lr has been investigated using advanced in-beam gamma-ray spectroscopic techniques. To date, 255Lr is the heaviest nucleus to be studied in this manner. One rotational band has been unambiguously observed and strong evidence for a second rotational structure was found. The structures are tentatively assigned to be based on the 1/2-[521] and 7/2-[514] Nilsson states, consistent with assignments from recently obtained alpha decay data. The experimental rotational band dynamic moment of inertia is used to test self-consistent mean-field calculations using the Skyrme SLy4 interaction and a density-dependent pairing force.

Fatty acids and ultrastructure of ozone-exposed Aleppo pine (Pinus halepensis Mill.) needles.

Fifteen or 18-month-old Aleppo pine seedlings were fumigated with different concentrations and doses of ozone over a period of 2-16 days in controlled-environmental growth chambers. The total fatty acid content and ultrastructure of the current year needles were subsequently analysed. In acute, high concentration exposures, significant reductions in the levels of linolenic acid were detected. Increases in myristic or palmitic acid were common in needles exposed to lower concentrations of ozone. Ultrastructural studies revealed reductions in chloroplast size and a darkening of stroma at low ozone exposures while at high concentrations disruption of the chloroplast membranes was also identified.

The effect of prostatic capsule perforation on the absorption of irrigating fluid during transurethral resection.

Thirty patients undergoing transurethral resection of the prostate using ethanol-tagged irrigating fluid were investigated in order to study the effects of a breach in the prostatic capsule. Measurements were made of end-tidal ethanol (ET-ethanol) in the expired air, serum glycine and sodium, haemoglobin, blood loss and volumetric determination of irrigating fluid absorption. Perforation of the prostatic capsule occurred in 13 patients (Group P), with 17 judged to have no perforation (Group NP). In all Group NP patients the ET-ethanol remained below 0.05/1000, serum sodium decreased by < or = 3 mmol/l and serum glycine remained < 1.5 mmol/l. ET-ethanol was significantly increased in Group P, rising to between 0.1 and 0.45/1000 in 5 patients, 3 of whom showed a reduction in serum sodium > 5 mmol/l. Five patients in Group P demonstrated significantly raised serum glycine concentrations up to 15 mmol/l. These findings suggest that perforation of the prostatic capsule may lead to rapid absorption of irrigating fluid, and that ET-ethanol monitoring is a useful method of detecting this quickly.

Synthesis and analysis of O,O'-dicarboxylate (dibenzyl) bispilocarpates as possible prodrugs of pilocarpine.

As a part of a series of studies to develop prodrug derivatives of pilocarpine, the O,O'-succinyl (dibenzyl), O,O-adipoyl (dibenzyl), O,O-fumaryl (dibenzyl), and O,O-terephthaloyl (dibenzyl) bispilocarpate fumarates were synthesized as a new class of pilocarpine prodrugs. The compounds were prepared from pilocarpic acid benzyl monoester by coupling two pilocarpic acid benzyl monoesters together with spacer chains by usual esterification methods. Liquid chromatography, thermospray liquid chromatography-mass spectrometry, high-resolution mass spectrometry, and NMR spectroscopy were applied to the identification and the purity evaluation of the synthetic products.

Improved corneal pilocarpine permeability with O,O'-(1,4-xylylene) bispilocarpic acid ester double prodrugs.

O,O'-(1,4-Xylylene) bispilocarpic acid esters are pilocarpine prodrugs containing two pilocarpic acid monoesters linked with one pro-moiety. Each mole of prodrug forms two pilocarpine moles in the presence of esterases. Corneal uptake and permeability of various bispilocarpic acid diesters were investigated in vitro using isolated albino rabbit corneas. The permeability coefficient of pilocarpine was 2.8 x 10(-6) cm/sec, whereas for bispilocarpic acid diesters, despite their large molecular weights (between 638 and 722), permeability coefficients were 6.5-20.2 x 10(-6) cm/sec. Only pilocarpine, and no intact prodrug, was observed at the endothelial side. Corneal uptake was increased with increasing lipophilicity, but a parabolic relationship between the logarithm of the apparent partition coefficient (1-octanol-pH 7.4 phosphate buffer) (log PC) and the corneal permeability was noticed. Corneal permeability and the rate of enzymatic hydrolysis of the compounds correlated well. The corneal permeability of pilocarpine given as lipophilic bispilocarpic acid diester (log PC greater than or equal to 3) prodrugs seems to be controlled by the formation of pilocarpine in the corneal epithelium rather than by the absorption of prodrugs into the epithelium or their epithelium-stroma transport rate.

Relative pharmacokinetics of three oral 400 mg ibuprofen dosage forms in healthy volunteers.

The pharmacokinetic properties of two solid form, 400 mg ibuprofen (IP) preparations, a soft gelatin capsule and a film-coated tablet, were compared to those obtained after the administration of liquid prepared from effervescent IP tablets. IP was absorbed rapidly (tmax 0.6-1.9 h). The fastest absorption was observed after the ingestion of the soft gelatin capsule; liquid and film-coated tablet produced 12.2-7.8 times longer absorption half-lives, 50-39% lower peak concentrations of IP in serum and 3.5-3.2 times higher tmax values. Bioavailabilities were close to similar after all products. All products were tolerated without side effects in this single-dose, crossover study on 14 healthy volunteers. The results of this study support the earlier findings that after oral administration, IP is absorbed equally well from solid formulations as from liquid form. Liquid formulations of IP often deliver slower absorption than expected probably due to incomplete dissolution of the active principle. This may have therapeutic significance, and it should be taken into account when studies on the relative bioavailability of IP from pharmaceutical drug products are planned.

Determination of physicochemical properties, stability in aqueous solutions and serum hydrolysis of pilocarpic acid diesters.

New alkyl and aralkyl pilocarpic acid diesters, prodrugs of pilocarpine, were synthesized with the aim of improving the bioavailability of pilocarpine by increasing its corneal permeability. These esters were several orders of magnitude more lipophilic than pilocarpine as determined by their apparent partition coefficients between 1-octanol and phosphate buffer (pH 7.40) (log P). Good correlation between log P and HPLC capacity factors of the compounds was observed. All the compounds are stable in acidic aqueous solution; in serum, however, pilocarpic acid diesters are hydrolysed enzymatically to pilocarpic acid monoester, which undergoes spontaneous cyclization to active pilocarpine and inactive isopilocarpine. The half-lives of the diesters in serum varied from 6-232 min. In addition to the direct effects of the R2, R1 moiety had a remarkable effect on the rate of enzyme-catalysed hydrolysis taking place in moiety R2. The formed pilocarpine was analysed with a new HPLC method which allowed good resolution of pilocarpine, isopilocarpine, pilocarpic acid and isopilocarpic acid. Rates for pilocarpine formation were both determined by experiment and calculated using the STELLA simulation programme with known degradation rate constants of pilocarpic acid diesters and monoesters. Since the simulations were in good agreement with the experimental results, it is concluded that STELLA simulation programme is useful in predicting pilocarpine formation.

Synthesis and identification of pilocarpic acid diesters, prodrugs of pilocarpine.

A series of new pilocarpic acid diesters were synthesized to obtain prodrugs for pilocarpine with varying physico-chemical properties. Thermospray liquid chromatography-mass spectrometry (TSP-LC-MS), liquid chromatography with UV-detection (LC-UV) and NMR-spectroscopy were used for the identification of the synthetic products and for evaluation of their purity including typical impurities (pilocarpic acid monoester, pilocarpine). TSP-LC-MS-analysis was performed in the reversed-phase mode using acetonitrile (60%)-0.2 M ammonium acetate (40%) as mobile phase. In LC-UV-analysis chromatographic separation was carried out on a reversed-phase column and the mobile phase consisted of methanol (71%) and 0.02 M potassium dihydrogen phosphate, pH 4.5 (29%). Electron ionization-mass spectrometry (EI-MS) was used for elucidation of structures. Elemental compositions of the substances were verified with high resolution-mass spectrometry (HR-MS). The complete establishment of structures presented was based on 1H-, and COSY-NMR-spectroscopy joined to TSP-LC-MS-analysis.

Bioavailability of doxycycline from dissolved doxycycline hydrochloride tablets--comparison to solid form hydrochloride tablets and dissolved monohydrate tablets.

Doxycycline (DC) is used either as solid form hydrochloride capsules, or as monohydrate tablets, which may be taken either as solid form tablets or dissolved in water. In this single dose (150 mg), crossover study on 15 healthy volunteers, the pharmacokinetic properties of DC from hydrochloride tablets taken either in dissolved or in solid form were compared with those observed after taking dissolved DC as a monohydrate tablet. The results of this study show that DC is absorbed rapidly (tmax 3.3-3.8 h) and with equal bioavailability (AUC values 52.9-58.5 mg/l x h) from both hydrochloride and monohydrate tablets. It can be concluded that taking the DC hydrochloride tablets in dissolved form does not affect the pharmacokinetics of DC, moreover the bioavailability of DC is comparable to that achieved after taking DC monohydrate tablets in dissolved form.

Pharmacokinetics of ibuprofen in man: a single-dose comparison of two over-the-counter, 200 mg preparations.

The pharmacokinetic properties of two 200 mg, over-the-counter (OTC) ibuprofen preparations were compared in a randomized crossover study on ten healthy volunteers. After 2 times 200 mg single dose, one preparation produced peak plasma ibuprofen concentration 30.0 +/- 2.1 micrograms/ml at 1.6 h and the other preparation 23.2 +/- 1.9 micrograms/ml at 2.3 h (p less than 0.05). There was no statistically significant difference between the preparations in the bioavailability of ibuprofen. OTC ibuprofen preparations are mainly used for acute indications, such as fever or headache. In these cases, rapid absorption and high concentrations of active ingredient are desirable properties, especially when the amount of drug is relatively low. Therefore, the pharmacokinetic differences between these preparations may be therapeutically significant.

Specific and sensitive quantitation of medroxyprogesterone acetate in human serum by gas chromatography-mass spectrometry.

A procedure for the quantitation of medroxyprogesterone acetate in serum using gas chromatography-quadrupole mass spectrometry is described. Medroxyprogesterone propionate, synthesized from medroxyprogesterone, was used as the internal standard. The serum samples were extracted on Bond Elut C18 cartridges, and the acetate and propionate were determined as their 3-enol heptafluorobutyrate esters by selected-ion monitoring technique. The linear range of the standard curve in serum was 0.5-30 ng/ml with a lower limit of quantitation of 0.5 ng/ml. The coefficient of variation of the method was 3.1% at 10 ng/ml and 5.5% at 1 ng/ml. The method is very rapid, and it has been applied for routine measurements of medroxyprogesterone acetate levels in human serum after oral administration of 10 or 20 mg.

Stimulation by oestradiol of the urinary excretion of perfluorooctanoic acid in the male rat.

The urinary excretion of perfluorooctanoic acid (PFOA) was studied in male Wistar rats after castration and oestradiol administration as well as in intact females and males. During the first 24 hr females excreted 72 +/- 5% (N = 6) of a single intraperitoneal dose of PFOA (50 mg/kg) in urine whereas the intact males excreted only 9 +/- 4% (N = 6). After castration followed by oestradiol administration (500 micrograms/kg every 2nd day for 14 days), the males excreted PFOA in urine in similar amounts as the females (68 +/- 14% at 24 hr, N = 10). Oestradiol treatment of non-castrated males produced similar results (61 +/- 19% at 24 hr, N = 10). Also castration without oestradiol administration significantly enhanced the renal PFOA excretion, but not as effectively as oestradiol treatment. After 96 hr, the concentration of PFOA in serum of intact males was 17-40 times higher than in the serum of other groups. PFOA was similarly bound by the proteins in the serum of females and males. Phase II metabolism of PFOA was not shown either in males or females.