Higher-order Laguerre-Gauss interferometry for gravitational-wave detectors with in situ mirror defects compensation

The use of higher-order Laguerre-Gauss modes has been proposed to decrease the influence of thermal noise in future generation gravitational-wave interferometric detectors. The main obstacle for their implementation is the degeneracy of modes with same order, which highly increases the requirements on the mirror defects, beyond the state-of-the-art polishing and coating techniques. In order to increase the mirror surface quality, it is also possible to act in situ, using a thermal source, sent on the mirrors after a proper shaping. In this paper we present the results obtained on a tabletop Fabry-Pérot Michelson interferometer illuminated with a LG_(3,3) mode. We show how an incoherent light source can reduce the astigmatism of one of the mirrors, increasing the quality of the beam in one of the Fabry-Pérot cavities and then the contrast of the interferometer. The system has the potential to reduce more complex defects and also to be used in future gravitational-wave detectors using conventional Gaussian beams

REDUCED CARDIOTOXICITY AND INCREASED CYTOTOXICITY IN A NOVEL ANTHRACYCLINE ANALOG, 4'-AMINO-3'-HYDROXY-DOXORUBICIN

The acute and chronic cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4'-amino-3'-hydroxy-DXR were compared with those of 4'-deoxy-DXR and DXR. In the acute cardiotoxicity study, the ECG and hemodynamic changes recorded in anesthetized rats that had been treated i.v. with 10 mg/kg 4'-amino-3'-hydroxy-DXR or 8.6 mg/kg 4'-deoxy-DXR were significantly less severe than those caused by 13 mg/kg DXR. In the chronic cardiotoxicity study, rats received 3 weekly i.v. injections of 3 mg/kg DXR, 3 mg/kg 4'-amino-3'-hydroxy-DXR, or 2 mg/kg 4'-deoxy-DXR during the first 14 days of the study and were observed for an additional 35-day period. DXR induced severe cardiomyopathy that was characterized by ECG changes in vivo (S-alpha-T-segment widening and T-wave flattening) and by impairment of the contractile responses (F(max), +/- dF/dt(max)) to adrenaline of hearts isolated from treated animals. 4'-Deoxy-DXR caused a progressive enlargement of the S-alpha-T segment in vivo and a significant impairment of the - dF/dt(max) value in vitro, which were less severe than those produced by DXR. The least cardiotoxic drug was 4'-amino-3'-hydroxy-DXR, which induced minor ECG changes without causing significant alterations in the contractile responses of isolated hearts to adrenaline. On the basis of the drug concentration required to inhibit 50% of the colony formation (IC50) of cell lines in vitro, 4'-amino-3'-hydroxy-DXR was less active than 4'-deoxy-DXR but at least twice as active as DXR against human cancer and murine transformed cell lines. These data indicate that 4'-amino-3'-hydroxy-DXR is significantly less cardiotoxic and more cytotoxic than DXR

Comparative distribution of azithromycin in lung tissue of patients given oral daily doses of 500 and 1000 mg

OBJECTIVES: The administration of antibacterial agents should be optimized on the basis of their distribution to enhance drug exposure and obtain bacterial eradication. This study examines the pharmacokinetics of azithromycin in plasma, lung tissue and bronchial washing in patients after oral administration of 500 mg versus 1000 mg once daily for 3 days. PATIENTS AND METHODS: Samples of plasma, lung tissue and bronchial washing were obtained from a cohort of 48 patients during open-chest surgery for lung resection up to 204 h after the last drug dose, and assayed for antibiotic concentrations. RESULTS: Azithromycin was widely distributed within the lower respiratory tract and sustained levels of the drug were detectable at the last sampling time in lung tissue. Doubling the dose of the antibiotic resulted in a proportional increase in lung area under the curve (AUC, 1245.4 versus 2514.2 h x mg/kg) and peak tissue concentration (Cmax, 8.93 +/- 2.05 versus 18.6 +/- 2.20 mg/kg). The pharmacodynamic parameter AUC/MIC for susceptible and intermediate strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L, respectively) increased after administration of the 1000 mg schedule compared with 500 mg (AUC/MIC0.5 2414 versus 1144 and AUC/MIC2 2112 versus 814.1 h x mg/kg, respectively) in pulmonary tissue. CONCLUSIONS: Lung exposure to azithromycin is increased proportionally by doubling the dose, which results in a predictable pharmacokinetic behaviour of the drug in the lower respiratory tract

Pharmacokinetics, a main actor in a many-sided approach to severe 5-FU toxicity prediction

Based on this clinical experience, we detail the principles that should guide the decision-making process regarding the prevention of 5-FU severe toxicity and propose a diagnostic algorithm in order to screen candidate patients to fluoropyrimidine therapy. In the suggested diagnostic algorithm, the predictive 5-FU test dose could be regarded as a triage test, allowing detection of the fraction of patients with normal, impaired or absent fluoropyrimidine metabolism. Other analyses, such as DPD genotyping or even DPD PBMC activity, could be used later as add-on tests and, limited to the still undiagnosed subgroup, to detect those degrees of enzyme activity impairment suitable for possible reduction of 5-FU dose or different treatments. Overall, the published data strongly suggest the use of a diagnostic algorithm based on the sequential application of a 5-FU pharmacokinetic test followed by DPD genotyping and activity in order to make a highly probable diagnosis of altered 5-FU metabolism. Moreover, the application of this model could result in a consistent reduction of costs and morbidity, by limiting genotyping and PBMC DPD activity analysis to only selected subgroups of patients

Exploiting the Pyrazolo[3,4-d]pyrimidin-4-one ring system as a useful template to obtain potent adenosine deaminase inhibitors,

A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/ subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2- yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4- dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure-activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors

Exploiting the Pyrazolo[3,4-d]pyrimidin-4-one ring system as a useful template to obtain potent adenosine deaminase inhibitors,

A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/ subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2- yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4- dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure-activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors

Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naïve patients with advanced non-small-cell lung cancer

Background. Gemcitabine (GEM) and paclitaxel (TAX) are active, non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performed a phase I study to determine the maximum-tolerated dose (MTD), antitumor activity and pharmacokinetics of GEM and TAX given weekly in chemo-naive patients with advanced NSCLC. Patients and methods: Escalating doses of GEM (800-2000 mg/m(2)) and TAX (60-100 mg/m(2)) were administered on days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasma pharmacokinetics of TAX and GEM was assessed at the three higher dose-levels. Results: Dose-escalation was discontinued in absence of MTD because of increased cumulative toxicity leading to dose modification or treatment delay at levels 6 and 7 (TAX 100 mg/m(2) plus GEM 1750 and, respectively, 2000 mg/m(2)). Hematological toxicity included grade 4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycle and febrile neutropenia in three cycles. Maximal non-hemathological toxicity was grade 3 elevation in serum transaminases and grade 2 neuro-sensory toxicity in 8% and 5% of cycles, respectively. At the two higher dose-levels a non-linear pharmacokinetics of GEM was observed with a remarkable variability of C-max and AUG. No pharmacokinetic interactions were reported. Objectives responses were seen at all dose levels, with an overall response rate of 43% (95% confidence interval (95% CI): 25.5%-62.6%) in 30 evaluable patients. Conclusions: The weekly administration of GEM and TAX is very well tolerated, and has shown promising antitumor activity in NSCLC. In view of the cumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg/m(2) of GEM and 100 mg/m2 of TAX are recommended for phase II studies

A First Search for coincident Gravitational Waves and High Energy Neutrinos using LIGO, Virgo and ANTARES data from 2007

We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.Comment: 19 pages, 8 figures, science summary page at http://www.ligo.org/science/Publication-S5LV_ANTARES/index.php. Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p120000