Synthesis and biological evaluation of novel pyridazine analogues (3-aldehyde-1-phenylpyridazine derivatives)

Five new pyridazine compounds were synthesized. The usefulness of IR, 1HNMR and 13CNMR spectroscopy for the structural analysis of the new compounds is well established. The differences in molecular structure between one absorbing compound and another affected a shift in absorption wavelength (.max). The structure-activity relationship among the pyridazine derivatives was measured against some pathogens. Compound 3e was found to be a more active drug than the standard antibiotic, streptomycin SO4. © 2010 International Formulae Group. All rights reserved.Keywords: Biological evaluation, novel, pyridazine derivatives, antimicrobial agents

Metacognitive Therapy for Depression in Adults: A Waiting List Randomized Controlled Trial with Six Months Follow-Up

This randomized controlled trial examines the efficacy of metacognitive therapy (MCT) for depression. Thirty-nine patients with depression were randomly assigned to immediate MCT (10 sessions) or a 10-week wait list period (WL). The WL-group received 10 sessions of MCT after the waiting period. Two participants dropped out from WL and none dropped out of immediate MCT treatment. Participants receiving MCT improved significantly more than the WL group. Large controlled effect sizes were observed for both depressive (d = 2.51) and anxious symptoms (d = 1.92). Approximately 70–80% could be classified as recovered at post-treatment and 6 months follow-up following immediate MCT, whilst 5% of the WL patients recovered during the waiting period. The results suggest that MCT is a promising treatment for depression. Future controlled studies should compare MCT with other active treatments

Âges K-Ar de glauconites des environs de Luz de Tavira, Algarve

Glauconite K-Ar ages (6.88±0.4; 7.03±0.4 MY) confirm earlier reports to Upper Tortonian of silt beds near Morgadinho, Luz de Tavira and Tavira. Taking stratigraphical position and age into account it is possible now to correlate these beds with similar ones at Quelfes and Cacela (Formação de Cacela, lower member, ascribed to the upper part of N16 or to NI7 Blow's zone, Globorotalia humerosa - G. dutertrei; Tortonian to Messinian, according to the ostracod fauna). Limit between the above quoted zones is thus placed at about 7 MY. New K-Ar ages greatly improve the knowledge about Upper Miocene in eastern Algarve, and on regional tectonic evolution. This is particulary so in what concerns an intra-Tortonian phase

Autoimmune Cholangitis in the SJL/J Mouse is Antigen Non-specific

Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by intrahepatic bile duct destruction and the production of anti-mitochondrial antibodies (AMA). The absence of an animal model has been a striking impedance in defining the molecular basis of disease. Previous work has suggested that SJL/J mice immunize with the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC, leads to the development of lymphoid cell infiltration in portal tracts and a model system coined autoimmune cholangitis. We hypothesized that this pathology would be augmented if immunization occurred in the presence of IFN-γ injections. Accordingly, SJL/J mice were immunized with PDC-E2 and, for purpose of control, α-casein. Subgroups of mice were also treated with exogenous IFN-γ. As expected, mice immunized with PDC-E2, with or without IFN-γ, developed high titer AMAs. In contrast, mice immunized with α-casein, develop antinuclear antibodies. More importantly, the livers from mice immunized with PDC-E2 and/or those immunized with α-casein all displayed lymphoid cell infiltration to the portal tracts, irrespective of bile duct size. Indeed, there was no significant difference between the experimental and the control groups by histologic analysis. Thus, autoimmune cholangitis in these mice is antigen non-specific

Isotopic ratios of H, C, N, O, and S in comets C/2012 F6 (Lemmon) and C/2014 Q2 (Lovejoy)

The apparition of bright comets C/2012 F6 (Lemmon) and C/2014 Q2 (Lovejoy) in March-April 2013 and January 2015, combined with the improved observational capabilities of submillimeter facilities, offered an opportunity to carry out sensitive compositional and isotopic studies of the volatiles in their coma. We observed comet Lovejoy with the IRAM 30m telescope between 13 and 26 January 2015, and with the Odin submillimeter space observatory on 29 January - 3 February 2015. We detected 22 molecules and several isotopologues. The H$_2^{16}$O and H$_2^{18}$O production rates measured with Odin follow a periodic pattern with a period of 0.94 days and an amplitude of ~25%. The inferred isotope ratios in comet Lovejoy are $^{16}$O/$^{18}$O = 499 $\pm$ 24 and D/H = 1.4 $\pm$ 0.4 $\times 10^{-4}$ in water, $^{32}$S/$^{34}$S = 24.7 $\pm$ 3.5 in CS, all compatible with terrestrial values. The ratio $^{12}$C/$^{13}$C = 109 $\pm$ 14 in HCN is marginally higher than terrestrial and $^{14}$N/$^{15}$N = 145 $\pm$ 12 in HCN is half the Earth ratio. Several upper limits for D/H or 12C/13C in other molecules are reported. From our observation of HDO in comet C/2014 Q2 (Lovejoy), we report the first D/H ratio in an Oort Cloud comet that is not larger than the terrestrial value. On the other hand, the observation of the same HDO line in the other Oort-cloud comet, C/2012 F6 (Lemmon), suggests a D/H value four times higher. Given the previous measurements of D/H in cometary water, this illustrates that a diversity in the D/H ratio and in the chemical composition, is present even within the same dynamical group of comets, suggesting that current dynamical groups contain comets formed at very different places or times in the early solar system.Comment: Accepted for publication in Astronomy and Astrophysic

The late stage of Parkinson's –results of a large multinational study on motor and non-motor complications

INTRODUCTION: There is little information on the late stages of parkinsonism. METHODS: We conducted a multicentre study in 692 patients with late stage parkinsonism in six European countries. Inclusion criteria were disease duration of ≥7 years and either Hoehn and Yahr stage ≥4 or Schwab and England score of 50 or less. RESULTS: Average disease duration was 15.4 (SD 7.7) years and mean total UPDRS score was 82.7 (SD 22.4). Dementia according to MDS-criteria was present in 37% of patients. Mean levodopa equivalence dose was 874.1 (SD 591.1) mg/d. Eighty two percent of patients reported falls, related to freezing (16%) or unrelated to freezing (21% of patients) or occurring both related and unrelated to freezing (45%), and were frequent in 26%. Moderate-severe difficulties were reported for turning in bed by 51%, speech by 43%, swallowing by 16% and tremor by 11%. Off-periods occurred in 68% and were present at least 50% of the day in 13%, with morning dystonia occurring in 35%. Dyskinesias were reported by 45% but were moderate or severe only in 7%. Moderate-severe fatigue, constipation, urinary symptoms and nocturia, concentration and memory problems were encountered by more than half of participants. Hallucinations (44%) or delusions (25%) were present in 63% and were moderate-severe in 15%. The association with overall disability was strongest for severity of falls/postural instability, bradykinesia, cognitive score and speech impairment. CONCLUSION: These data suggest that current treatment of late stage parkinsonism in the community remains insufficiently effective to alleviate disabling symptoms in many patients

Scientific and Regulatory Policy Committee (SRPC) Review*: Interpretation and Use of Cell Proliferation Data in Cancer Risk Assessment

Increased cell proliferation is a central key event in the mode of action for many non-genotoxic carcinogens, and quantitative cell proliferation data play an important role in the cancer risk assessment of many pharmaceutical and environmental compounds. Currently, there is limited unified information on assay standards, reference values, targeted applications, study design issues, and quality control considerations for proliferation data. Here, we review issues in measuring cell proliferation indices, considerations for targeted studies, and applications within current risk assessment frameworks. As the regulatory environment moves toward more prospective evaluations based on quantitative pathway-based models, standardiza- tion of proliferation assays will become an increasingly important part of cancer risk assessment. To help address this development, we also discuss the potential role for proliferation data as a component of alternative carcinogenicity testing models. This information should improve consistency of cell proliferation methods and increase efficiency of targeted testing strategies

Observation of water vapor in the stratosphere of Jupiter with the Odin Space Telescope.

International audienceThe water vapor line at 557 GHz has been observed with the Odin space telescope with a high signal-to-noise ratio and a high spectral resolution on November 8, 2002. The analysis of this observation as well as a re-analysis of previously published observations obtained with the SubmillimeterWavelength Astronomy Satellite seem to favor a cometary origin (Shoemaker-Levy 9) for water in the stratosphere of Jupiter, in agreement with the ISO observation results. Our model predicts that the water line should become fainter and broader from 2007. The observation of such a temporal variablity would be contradictory with an IDP steady flux, thussupporting the SL9 source hypothesis