Synthesis and biological activity of 5-(2,2-difluorocyclopropyl)-2'-deoxyuridine deoxyuridine diastereomers.

The synthesis of the two diastereomers (9 and 10) of 5-(2,2-difluorocyclopropyl)-2'-deoxyuridine are described. Their antiviral and cytotoxic activities were determined, in comparison with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 5-fluoro-2'-deoxyuridine (FDU), respectively. 5-[(1R)-2,2-Difluorocyclopropyl]-2'-deoxyuridine (10) was the most active antiviral agent against HSV-1 (IC50 = 5 micrograms/ml) relative to BVDU (IC50 = 0.082 micrograms/ml), and cytotoxic agent in the CCRF-CEM (IC50 = 230 microM) screen relative to FDU (IC50 = 4.7 x 10(-3) microM). The 5-[(1S)-2,2-difluorocyclopropyl] diastereomer was inactive in both screens. Partition coefficients (P) and affinity for the mouse erythrocyte nucleoside transporter (Ki) were not determinants of antiviral or cytotoxic activities. However, the (1R)-diastereomer (10) was more resistant to glycosidic bond cleavage by thymidine phosphorylase than the (1S)-diastereomer (9).     

Synthesis of 131I, 125I and 82Br labelled (E)-5-(2-halovinyl)-2'-deoxyuridines

Radiohalogenated (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU, 4) and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, 5) were synthesized by reaction of (E)-5-(2-carboxyvinyl)-2'-deoxyuridine (1) with radiolabelled iodide or bromide in the presence of chloramine-T. A "no-carrier-added" synthesis of [131I]IVDU was completed within 30 min providing a radiochemical yield of 65%. Alternatively, radioactive iodine was incorporated into IVDU using a halogen isotope exchange reaction catalyzed by cuprous ion. [82Br]BVDU was also prepared by direct neutron activation of unlabelled BVDU.     

Tumor uptake of radiolabelled pyrimidine bases and pyrimidine nucleosides in animal models: VI. 1-(3'-[36Cl]-chloro-, 1-(3'-[82Br]-bromo- and 1-(3'-[123I]-Iodo-3'-deoxy-beta-D-arabinofuranosyl)uracil

3'-Radiohalogenated (36Cl, 82Br and 123I) "arabino" pyrimidine nucleosides were evaluated as potential tumor diagnostic agents in tumor bearing animals. No preferential tissue uptake was observed. The compounds were excreted mainly unchanged in the urine. The 3'-[36Cl]- and 3'-[82Br]-3'-deoxyarabino nucleosides exhibited biliary uptake. The low uptake of injected radioactivity by the tumor was probably due to the combined effects of the lack of a C-3' hydroxyl group in the "ribo" configuration, the presence of a halogen, the structural rigidity imposed by the presence of a halogen and the short biological half-lives of the compounds.     

The expanding role of ICU medical directors: from patient management to unit management

Over the past three decades the focus of physicians delivering intensive care has been on patient management whereas the management of critical care units has been done primarily by nurses. This article reviews existing literature and the arguments supporting a more active role for physicians in the management of critical care units.     

An evaluation of outcome from intensive care in major medical centers

We prospectively studied treatment and outcome in 5030 patients in intensive care units at 13 tertiary care hospitals. We stratified each hospital's patients by individual risk of death using diagnosis, indication for treatment, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. We then compared actual and predicted death rates using group results as the standard. One hospital had significantly better results with 69 predicted but 41 observed deaths (p less than 0.0001). Another hospital had significantly inferior results with 58% more deaths than expected (p less than 0.0001). These differences occurred within specific diagnostic categories, for medical patients alone and for medical and surgical patients combined, and were related more to the interaction and coordination of each hospital's intensive care unit staff than to the unit's administrative structure, amount of specialized treatment used, or the hospital's teaching status. Our findings support the hypothesis that the degree of coordination of intensive care significantly influences its effectiveness.     

Identification of low-risk monitor admissions to medical-surgical ICUs

A total of 5,790 intensive care unit (ICU) admissions from 13 tertiary care institutions were studied to identify patients who were at such low risk of receiving unique ICU therapies that admission might have been avoided or the length of ICU stay reduced. We used acute severity of disease on admission to the ICU along with the type of disease or surgery to risk stratify individual ICU patients. Among 1,941 patients who only received monitoring services on admission to the ICU, 1,358 (70 percent) were predicted to have less than a 10 percent risk of requiring subsequent active ICU treatment. Only 58 (4.3 percent) of these low-risk patients actually received active treatment. The identification of low-risk patients was equally accurate in estimation and validation data sets. Our methods should allow physicians and hospitals to assess their current ICU utilization and, if appropriate, guide reductions in use.     

Characterisation of ecto- and endoparasites in domestic cats from Tirana,Albania

During 2008 to 2011, faecal samples, ear swabs, and ectoparasites obtained by full body search and total body comb were collected from 252 cats originating from the greater Tirana area. Faecal samples were examined using the McMaster and Baermann techniques, and a subset of 58 samples was tested for Giardia-specific antigen using a coproantigen enzyme-linked immunosorbent assay (ELISA). The ear swabs were examined for the presence of parasitic mites. Overall, almost 93 % of the cats were identified harbouring one or more parasites: 59.1 % (95 % confidence interval (CI), 53.0–65.0) and 86.9 % (95 % CI, 82.7–91.1) of the cats tested positive for ecto- or endoparasites, respectively; 53.2 % of the cats had evidence for concomitant ectoparasite infestation and endoparasite infection. For ectoparasite infestation, prevalence was 52.0 % for total fleas (Ctenocephalides felis, 51.2 %; Ctenocephalides canis, 2.0 %; and Leptopsylla segnis, 0.4 %), 8.3 % each for Felicola subrostratus and Otodectes cynotis and 4.0 % for Rhipicephalus sanguineus sensu lato. The most prevalent endoparasites were Toxocara ascarids (48.0 %), followed by Aelurostrongylus lungworms (39.7 %), Capillaria spp. (31.7 %), hookworms (32.9 %), dipylidiid cestodes (27.8 %), Cystoisospora spp. (23.4 %) and taeniid cestodes (2.0 %). One animal was found shedding Pseudamphistomum truncatum eggs. Giardia-specific antigen was detected in 29.3 % of the 58 cats tested. Mixed infections with up to six endoparasites concurrently (excluding Giardia) and mixed infestations with two or three species of ectoparasites were recorded in 73.1 and 22.8 % of the parasite-positive cats, respectively. Cats ≤9 months of age were more frequently tested (p?Toxocara and Cystoisospora infections than cats >9 months while these cats tested more often (p?Aelurostrongylus-positive compared with the younger cats. The prevalence of infestation with ectoparasites did not differ between the cats of these two age groups. Given the impact that some of the parasites may have upon animal health as well as the zoonotic potential of some of them, measures should be taken to minimise the transmission of these parasites.