The Italian START-Register on Anticoagulation with Focus on Atrial Fibrillation

START-Register – Survey on anTicoagulated pAtients RegisTer – is an independent, inception-cohort, observational, collaborative database aimed at recording prospectively the clinical history of adult patients starting anticoagulant treatment for any reason and using whatever drug. In this article we present the START-Register and give cross section baseline data focusing on non valvular atrial fibrillation (NVAF). Participants are asked to insert prospectively consecutive patients recorded as electronic file on the web-site of the registry. Required data are: demographic and clinical characteristics of patients, associated risk factors for stroke and bleeding, laboratory routine data, clinical indication for treatment, expected therapeutic range (in cases of treatment with vitamin K antagonists -VKAs). The follow-up is carried out to record: quality of treatment (for patients on VKAs), bleeding complications, thrombotic events, and the onset of any type of associated disease. To date 5252 patients have been enrolled; 97.6% were on VKAs because direct oral anticoagulants (DOAC) have been available in Italy only recently. The median age was 74 years [interquartile range (IQR) 64-80]; males 53.7%. This analysis is focused on the 3209 (61.1%) NVAF patients. Mean CHADS₂ score was 2.1±1.1, CHADSVASc score was 3.1±1.3;median age was 76 years (IQR 70-81); 168 patients (5.3%) had severe renal failure [Creatinine clearance (CrCl) <30 ml/min]. Moderate renal failure (CrCl 30-59 ml/min) was found in 1265 patients (39.5%). The analysis of the START-Register data shows that two-third of patients who started chronic anticoagulant treatment had NVAF, one-third of them was > 80 years with high prevalence of renal failure.     

Synthesis and antiproliferative activity of basic thioanalogues of merbarone

Three series of 5-substituted 1,3-diphenyl-6-(omega-dialkyl- and omega-cyclo-aminoalkyl)thio-2-thiobarbiturates (11-13) were synthesized as polysubstituted thioanalogues of merbarone, a topoisomerase II inhibitor acting on the catalytic site. To better understand pharmacophore requirements, a forth series of conformationally constrained analogues 14 was also prepared. Derivatives 11b,e, 14b,e,h,i,j were active in the low micromolar concentration range (IC(50): 3.3-4.3 microM), whereas compounds 11a,c,d,f,h,j and 13a,b,d,g,j and 14a,d,f showed IC(50) values between 10 and 15.5 microM. In contrast, compounds 12a-c,g-j, 13e,f,h and 14k were inactive. Cytotoxicity data provided from N.C.I. on selected compounds provided evidence that 11b,d, 13d,g and 14b,d,f,h,i,j were endowed with potent antiproliferative activity against leukemia and prostate cell lines (GI(50) up to 0.01 microM). In general, bicyclic derivatives 14 were up to 10-fold more potent than monocyclic counterparts against solid tumor-derived cell lines. SAR studies indicated that, in general, a certain tolerability in length of the alkyl side chains and in shape of distal amines is allowed in the four series, but in the monocyclic derivatives (11-13) antiproliferative activity was strongly affected by the nature of the 5-substituents (COOC(2)H(5)>COCH(3)>C(6)H(5)). Compounds 11b and 14b were also evaluated against KB cell subclones expressing altered levels of topoisomerases or the multidrug resistance phenotype (MDR). In both cases the above compounds showed a decrease in potency. In enzyme assays, 11b and 14b turned out to be inhibitors of topoisonerase II as merbaron.     

Chemical Composition and Antifungal Activity of Essential Oils and Supercritical CO2 Extracts of Apium nodiflorum (L.) Lag.

Aerial parts of Apium nodiflorum collected in Portugal and Italy were submitted to hydrodistillation; also a supercritical fluid extract was obtained from Italian plants. The extracts were analyzed by GC and GC/MS. Both essential oils, obtained from Portuguese and Italian plants, posses high content of phenylpropanoids (51.6 vs. 70.8%); in the former, the percentage split in myristicin (29.1%) and dillapiol (22.5%), whereas in the latter, the total percentage is only of dillapiol (70.8%). The co-occurrence of myristicin and dillapiol is frequent because dillapiol results from enzymatic methoxylation of myristicin. Antimicrobial activity of phenylpropanoids has been patented, what suggest the potential of plants with high amounts of these compounds. Minimal inhibitory concentration (MIC) and minimal lethal concentration, determined according to NCCLS, were used to evaluate the antifungal activity of the essential oils against yeasts, Aspergillus species and dermatophytes. Essential oils exhibited higher antifungal activity than other Apiaceae against dermatophytes, with MIC ranging from 0.04 to 0.32?μl/ml. These results support the potential of A. nodiflorum oil in the treatment of dermatophytosis and candidosis.     

Comparison of Worm Control Strategies in Grazing Sheep in Denmark

Control of nematode parasites with reduced reliance on the use of anthelmintics was studied in 16 ewes with suckling twin lambs on contaminated pasture in Denmark. Ewes and lambs were treated with albendazole at turn-out 3 May. Ewes were removed from the groups on 26 July, and lambs were slaughtered on 11 October. The animals were allocated to 4 groups of 8 lambs and their 4 ewes. Group TS was treated with albendazole at weeks 3, 6 and 8 after turnout and set-stocked; group TM was similarly treated but moved to clean pasture in conjunction with the last drenching; group US was untreated and set-stocked, and group UM was left untreated but moved to clean pasture week 8 after turn-out. Supplementary feed was offered in June and August due to scarcity of pasture. Strategic treatments of ewes and lambs weeks 3, 6 and 8 after turn-out, with or without a move to clean pasture, were highly effective in controlling nematode infections for most of the season. This was reflected in better weight gains and carcass characteristics in the treated compared to untreated lambs, resulting in an average increase in the value of the product by 36%. The effect of moving without treatment (UM) on faecal egg counts was limited but peak pasture infectivity was reduced to less than 10% compared to the set-stocked group and weight gains of lambs were significantly better despite poor feed availability in late season. The study showed that under set-stocked conditions repeated anthelmintic treatments of both ewes and lambs in early season may ensure sufficient nematode control whereas moving animals to clean pasture without dosing was less efficient. The latter may, however, still be a viable option in organic and other production systems where routine use of anthelmintics is banned, particularly if weaning and moving are combined or a second move is performed.     

Life‐history traits of the long‐nosed skate Dipturus oxyrinchus

This work investigates life‐history traits of the long‐nosed skate Dipturus oxyrinchus, which is a common by‐catch in Sardinian waters. The reproductive variables were analysed from 979 specimens sampled during scientific and commercial hauls. Females (10·4–117·5 cm total length, L_T) attained larger sizes than males (14·5–99·5 cm L_T). To evaluate age and growth, a sub‐sample of 130 individuals (76 females and 54 males) were used. The age was estimated by annuli counts of sectioned vertebral centra. Four models were used for the length‐at‐age data: the von Bertalanffy, the exponential, the Gompertz and the logistic functions. According to the Akaike's information criterion, the Gompertz model seemed to provide the best fitting curve (L_∞ mean ± s.e. : 127·55 ± 4·90 cm, k: 0·14 ± 0·09, IP: 3·97 ± 0·90 years). The oldest female and male were aged 17 (115·5 cm L_T) and 15 years (96·0 cm L_T), respectively. Lengths at maturity were 103·5 cm for females and 91·0 cm for males, corresponding to 90% of the maximum observed length in both sexes. The monthly distribution of maturity stages highlighted an extended reproductive cycle, with spawning females and active males being present almost throughout the year, as confirmed by the gonado‐somatic index. Ovarian fecundity reached a maximum of 26 yolked follicles with a mean ± s.e. size of 19·7 ± 6·5 mm.     

Investigation of apoptosis in cultured cells infected with equine herpesvirus 1

Many viruses alter different stages of apoptosis of infected cells as a strategy for successful infection. Few studies have addressed mechanisms of equine herpesvirus 1 (EHV-1) strain-induced cell death. We investigated the effect of an abortigenic strain (AR8 strain) on heterologous Madin–Darby bovine kidney cells and homologous equine dermis (ED) cells cell lines. We compared morphologic and biochemical features of early and late apoptosis at different postinfection times. We investigated translocation of phosphatidylserine to the cell surface, nuclear fragmentation and changes in the cytoskeleton using flow cytometry and annexin V/propidium iodide staining, DNA laddering, terminal deoxynucleotidyl transferase UTP nick-end labeling assay and immunofluorescence staining of cytokeratin 18 cleavage. AR8 EVH-1 strain interfered with apoptosis in both cell lines, particularly during the middle stage of the replication cycle; this was more evident in ED cells. Although this antiapoptotic effect has been reported for other alpha herpesviruses, our findings may help elucidate how EHV-1 improves its infectivity during its cycle.