Mucosal permeability of water-soluble drugs in the equine jejunum: a preliminary investigation

Ussing chambers have been used to study the mucosal permeability of drugs in humans, rats and other species. This data can then be used to develop in vitro/in vivo correlations (IVIVC) for drugs based on the Biopharmaceutics Classification System (BCS). Due to the poor oral bioavailability of many drugs in the horse, this method may be useful for screening drugs before development to determine if they warrant further study. Cephalexin (CPX), marbofloxacin (MAR), metronidazole (MTZ) and fluconazole (FCZ) were chosen for this study based on the wide range of physicochemical properties and bioavailability in the horse. Permeability was ranked as follows: MTZ > FCZ > MAR > CPX. This correlated with the bioavailability (R(2) = 0.633447), the Log P (R(2) = 0.648517), as well as the molecular weight (R(2) = 0.851208) of the drugs. Metronidazole induced a decrease in the tissue transepithelial resistance, suggestive of the possibility of tissue toxicity, which may have falsely increased its permeability. The low permeability of cephalexin across the tissue may indicate a lack of active transporters that are found in other species. From this study, we can conclude that the Ussing chamber is a promising method for determining mucosal permeability in the horse.     

Median sternotomy closure in dogs: a mechanical comparison of technique stability

OBJECTIVE: To evaluate the mechanical properties of canine median sternotomy closure using double-loop cerclage compared with other commonly used cerclage sternotomy closure patterns. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Forty canine cadaveric sternal segments. METHODS: Median sternotomy-wire constructs were loaded to failure in a materials testing machine. Each construct was radiographed before and after testing. Specific wire configurations tested were: 2 single twist cerclage centered on the sternebrae, single twist figure of 8 pattern centered on the sternal synchondrosis, double twist figure of 8 pattern centered on the sternal synchondrosis, 2 double-loop cerclage centered on the sternebrae, and 1 double-loop cerclage centered on the sternal synchondrosis. Wire configurations were compared by craniocaudal translation of sternabrae on pre-test radiographs, and displacement during loading, and mode of failure, based on analysis of test video, and post-test radiographs. RESULTS: Double-loop cerclage did not provide superior mechanical stabilization of median sternotomy. Both figure of 8 patterns had the least displacement at higher loads. Two single twists that were centered on sternebrae were least able to prevent displacement at higher loads, caused the most craniocaudal translation before testing, and fractured more often at loads < or = 200 N compared with other configurations. CONCLUSION: Sternal wiring techniques stabilizing sternal synchondroses had the least displacement. Overall, figure of 8 cerclage appeared most suitable because they minimized displacement at high loads and facilitated accurate reduction during tensioning. CLINICAL RELEVANCE: In closing canine sternotomy, figure of 8 cerclage may be most suitable. Double-loop cerclage centered on the sternal synchondrosis should be avoided because of wire failure at high loads.     

The efficacy of intratumoural 5-fluorouracil for the treatment of equine sarcoids

OBJECTIVE: To document the efficacy of intratumoural injections of 5-fluorouracil for the treatment of equine sarcoids. DESIGN: A prospective study that included 13 horses and one donkey. PROCEDURE: Sarcoids were confirmed by histological examination and treated with intratumoural 5-fluorouracil every 2 weeks. If the sarcoids did not resolve after seven treatments, treatment was considered a failure. All cases were re-examined 6 months after treatment commenced and owners were telephoned 3 years after commencement of treatment to report on tumour recurrence. Outcome comparisons were performed to determine the effect of previous treatment, tumour size and tumour location on sarcoid resolution. The efficacy of intratumoural 5-fluorouracil was compared with other previously documented treatments of equine sarcoids. RESULTS: Sarcoids smaller than 13.5 cm3 were significantly (P = 0.032) more likely to resolve with treatment than larger sarcoids. Sarcoids that were not responsive to previous therapies were significantly (P = 0.007) more likely to recur after 3 years than sarcoids that had not been treated prior to this study. In this study, there were similar rates of resolution in cases with mutiple tumours (66.6%) when compared to cases with single tumours (60%). The numbers in this study were too small to properly evaluate the effect of tumour location on the success of treatment. Intratumoural 5-fluorouracil appeared to have resolved sarcoids in 9 of 13 cases (61.5%) as determined by follow up conversation with the owners 3 years after the initial treatment. CONCLUSION: The use of intratumoural 5-fluorouracil compares favourably with other treatment modalities for sarcoids, with a long term successful resolution rate of 61.5%. Owners should be warned that resistant sarcoids and sarcoids larger than 13.5 cm3 have a poorer prognosis for resolution and more aggressive therapeutic options should be considered.     

Scrapie infection alters the distribution of plasma metabolites in diseased Cheviot sheep indicating a change in energy metabolism

Nuclear magnetic resonance (NMR) spectroscopy has been used to profile the metabolic status of plasma from; sheep showing clinical signs of scrapie, those known to be infected with scrapie but yet to show clinical signs, and control animals. The NMR measurements have shown that energy metabolism in scrapie infected animals is altered before the onset of clinical symptoms. These metabolic changes may provide the foundation for a pre-clinical diagnostic test for scrapie in sheep.     

Human IRGM induces autophagy to eliminate intracellular mycobacteria

Immunity-related p47 guanosine triphosphatases (IRG) play a role in defense against intracellular pathogens. We found that the murine Irgm1 (LRG-47) guanosine triphosphatase induced autophagy and generated large autolysosomal organelles as a mechanism for the elimination of intracellular Mycobacterium tuberculosis. We also identified a function for a human IRG protein in the control of intracellular pathogens and report that the human Irgm1 ortholog, IRGM, plays a role in autophagy and in the reduction of intracellular bacillary load.     

The competitive cost of antibiotic resistance in Mycobacterium tuberculosis

Mathematical models predict that the future of the multidrug-resistant tuberculosis epidemic will depend on the fitness cost of drug resistance. We show that in laboratory-derived mutants of Mycobacterium tuberculosis, rifampin resistance is universally associated with a competitive fitness cost and that this cost is determined by the specific resistance mutation and strain genetic background. In contrast, we demonstrate that prolonged patient treatment can result in multidrug-resistant strains with no fitness defect and that strains with low- or no-cost resistance mutations are also the most frequent among clinical isolates.     

Transatlantic abundance of the N2-fixing colonial cyanobacterium Trichodesmium

Colonial diazotrophic cyanobacteria of the genus Trichodesmium are thought to play a significant role in the input of new nitrogen to upper layers of the tropical and subtropical oceanic ecosystems that cover nearly half of Earth's surface. Here we describe results of a transatlantic survey in which a noninvasive underwater digital microscope (the video plankton recorder), was towed across the North Atlantic at 6 meters per second while undulating between the surface and 130 meters. Colony abundance had a basin-scale trend, a clear association with anticyclonic eddies, and was not affected by hurricane-forced mixing. Subsurface abundance was higher than previously reported, which has important implications for the global ocean nitrogen cycle.     

Infectious prions in the saliva and blood of deer with chronic wasting disease

A critical concern in the transmission of prion diseases, including chronic wasting disease (CWD) of cervids, is the potential presence of prions in body fluids. To address this issue directly, we exposed cohorts of CWD-na?ve deer to saliva, blood, or urine and feces from CWD-positive deer. We found infectious prions capable of transmitting CWD in saliva (by the oral route) and in blood (by transfusion). The results help to explain the facile transmission of CWD among cervids and prompt caution concerning contact with body fluids in prion infections.