Risk factors for Newcastle disease in broiler farms in Israel.

Following a large outbreak of Newcastle disease (ND) in Israel, a cross-sectional study was conducted in the broilers sector. The aim of the study was to find geographical and farm related risk factors for ND. Information was available on 96% of the broiler farms in Israel. Of these, farms diagnosed with ND in the years 2010-2012 were compared with the other farms. Risk factors for ND were analyzed, using Generalized Estimating Equation models. Six variables were found to be associated with the risk for ND outbreak: a distance of less than 300m from another farm (OR=1.77, 95% CI 1.07-2.93), a distance of less than 6000m from a national border (OR=2.00, 95% CI 1.22-3.30), farm location in the Ha'amakim district (OR=2.46, 95% CI 1.32-4.61), village type: a Moshav (village) vs. Kibbutz (Cooperative village) (OR=1.96, 95% CI 1.04-3.70), and carcass disposal in an uncovered bin (OR=1.96, 95% CI 1.18-3.26). A distance of less than 800m from an inter-city road was found to be a protective factor (OR=0.60, 95% CI 0.37-0.98). The results of this study provide information that may be used to improve surveillance and control of ND.

Integrating animal health and foodborne disease surveillance.

The control of foodborne diseases from an animal source has become an important part of public health policy. Since the agents that cause these diseases originate in animals, Veterinary Services, as well as Public Health Services, must be involved in their control. Control programmes should be established either through cooperation between the two Services or by the consolidation of all those involved into a single food control agency. Surveillance is an important part of these control programmes. The following questions must be addressed when planning an effective surveillance programme. What is the relative incidence, morbidity, mortality and economic cost of the foodborne disease in humans? Is the animal population the exclusive or a significant source of the human foodborne infection? What kind of surveillance is needed to identify the disease-causing agent in the animal population? Are we interested in identifying all cases of a disease in order to eradicate it or is our aim to reduce its incidence in the animal population? Do we have the ability to control the disease in the animal population? What disease detection tests are available? What are the sensitivity, specificity and cost of these diagnostic tests? Finally, does the country, region or agency involved have the legal, financial and educational resources to carry out this surveillance and follow it up with appropriate action? After these questions have been resolved,the veterinary and public health sectors must jointly decide if surveillance and control are feasible. If so, they can then begin to develop an appropriate programme.

Potent inhibition of thymidylate synthase by two series of nonclassical quinazolines.

The synthesis and biological activity of two series of nonclassical thymidylate synthase (TS) inhibitors are described. The first is a series of 10-propargyl-5,8-dideazafolic acid derivatives (10a-j) and the second is a series of the analogous 2-desamino derivatives (13a-c,k), both bearing a more lipophilic substituent on the phenyl ring than the CO-glutamate of classical antifolates. Compounds 10a-j were prepared in a straightforward manner, generally by treatment of N-[6-(bromomethyl)-3,4-dihydro-4-oxo-2-quinazolinyl]-2,2-dimethylprop anamide (6) with various phenyl-substituted N-propargylanilines (8), followed by deprotection. Compounds 13a-c,k were prepared similarly from [6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl] methyl 2,2-dimethylpropanoate (11). The compounds were tested for inhibition of purified L1210 TS and for inhibition of L1210 cell growth in vitro. Several of these nonclassical analogues approached the TS inhibitory potency of 10-propargyl-5,8-dideazafolic acid (1, CB3717), a glutamate-containing TS inhibitor. 2-Amino target compounds 10a-j were generally potent inhibitors of L1210 TS, with IC50s within the range of 0.51-11.5 microM, compared to 0.05 microM for 1. The order of potency for phenyl substitution at the 4-position in this series was the following: COCF3 greater than or equal to NO2 greater than or equal to CONH2 greater than or equal to COCH3 greater than SO2NMe2 greater than CN much greater than OCF3 greater than or equal to F. The 2-desamino target compounds 13a-c,k also exhibited significant, although diminished, TS inhibition. Both series were growth inhibitory to cells in tissue culture and this inhibition could be reversed by thymidine alone, indicating that the primary target was TS. None of the compounds was a potent inhibitor of dihydrofolate reductase. These studies indicate that the presence of the glutamate moiety in folate analogues is not an absolute requirement for potent inhibition of TS.

Benzothiopyranoindazoles, a new class of chromophore modified anthracenedione anticancer agents. Synthesis and activity against murine leukemias.

The synthesis of the benzothiopyranoindazoles, a new class of chromophore modified anthracenediones related to mitoxantrone, is described. In this structural class the quinone moiety, which is believed to be responsible for the cardiotoxicity of the anthracyclines, has been designed out. The synthesis of the benzothiopyranoindazoles was carried out by a multistep sequence from requisite 1-chloro-4-nitro-9H-thioxanthen-9-one precursors. Reaction with a monoalkylhydrazine gave a 5-nitrobenzothiopyranoindazole adduct, which was catalytically reduced to a corresponding C-5 anilino intermediate. Alkylation of 7 with a requisite X(CH2)nNR1R2 (X = Cl, Br; R1, R2 = H, alkyl, acyl; n = 2,3) provided target "two-armed" benzothiopyranoindazoles or A-ring methoxy and/or side chain acyl intermediates, which could be converted to 3 by appropriate deprotection methodologies. Alternatively, certain target compounds 3 were synthesized by reaction of 7 with appropriately functionalized glycine precursors under Schotten-Bauman or BOP chloride condensation conditions to provide C-5 acylamino intermediates, followed by Red-Al reduction and deprotection steps. Described also is the synthesis of selected benzothiopyranoindazole congeners with proximal acylamino side chains at C-5 and B-ring sulfone functionality at S-6. Potent activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-9) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by (a) a basic side chain at N-2 and a dibasic side chain at C-5 with primary or secondary distal amine substitution, (b) certain patterns of A-ring hydroxylation with 8-OH and 9-OH most favorable, and (c) sulfide oxidation state at S-6. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional broad-spectrum in vivo anticancer activity, selected compounds in this series have been chosen for development toward clinical trials.