The efficacy and adverse event profile of dexamethasone,melphalan, actinomycin D,and cytosine arabinoside (DMAC) chemotherapy in relapsed canine lymphoma

In this retrospective study, a chemotherapy protocol using dexamethasone, melphalan, actinomycin D, and cytosine arabinoside (DMAC) was evaluated for efficacy and adverse event profile as a first line rescue protocol in 86 client-owned dogs previously treated with a CHOP-based protocol. Forty-three dogs (43%) achieved remission (16% complete remission, 27% partial remission), and 57% were non-responders. The median overall progression-free survival (PFS) was 24 days. Adverse events included thrombocytopenia in 41% of dogs, neutropenia in 17% of dogs, and gastrointestinal toxicity in 13% of dogs. Overall, 16% (13/79) dogs experienced grade III to IV thrombocytopenia, 8% (6/74) dogs grade III to IV neutropenia and 1% (1/79) dogs grade III to IV gastrointestinal toxicity. The efficacy of the DMAC protocol is similar to that of other rescue protocols in dogs with relapsed lymphoma but is associated with shorter PFS. The main toxicity is thrombocytopenia, which may limit treatment.     

Influence of prior determination of baseline minimum alveolar concentration (MAC) of isoflurane on the effect of ketamine on MAC in dogs

The objective of this study was to determine if prior measurement of the minimum alveolar concentration (MAC) of isoflurane influences the effect of ketamine on the MAC of isoflurane in dogs. Eight mixed-breed dogs were studied on 2 occasions. Anesthesia was induced and maintained using isoflurane. In group 1 the effect of ketamine on isoflurane MAC was determined after initially finding the baseline isoflurane MAC. In group 2, the effect of ketamine on isoflurane MAC was determined without previous measure of the baseline isoflurane MAC. In both groups, MAC was determined again 30 min after stopping the CRI of ketamine. Plasma ketamine concentrations were measured during MAC determinations.In group 1, baseline MAC (mean ± SD: 1.18 ± 0.14%) was decreased by ketamine (0.88 ± 0.14%; P < 0.05). The MAC after stopping ketamine was similar (1.09 ± 0.16%) to baseline MAC and higher than with ketamine (P < 0.05). In group 2, the MAC with ketamine (0.79 ± 0.11%) was also increased after stopping ketamine (1.10 ± 0.17%; P < 0.05). The MAC values with ketamine were different between groups (P < 0.05). Ketamine plasma concentrations were similar between groups during the events of MAC determination.The MAC of isoflurane during the CRI of ketamine yielded different results when methods of same day (group-1) versus separate days (group-2) are used, despite similar plasma ketamine concentrations with both methods. However, because the magnitude of this difference was less than 10%, either method of determining MAC is deemed acceptable for research purposes.     

Helping working Equidae and their owners in developing countries: Monitoring and evaluation of evidence-based interventions

There are an estimated 112 million Equidae (horses, donkeys, mules) in the developing world, providing essential resources for their owners’ livelihoods and well-being. The impoverished situation of their owners and the often harsh conditions in which they work mean that the animals’ welfare is a cause for concern. A number of equine non-governmental organisations (NGOs) operate within working equid communities providing veterinary care, education and training programmes aimed at improving equine welfare. However, there is little published information available that describes monitoring and evaluation (M&E) of such interventions using objective outcome-based indicators and where baseline data are available. The aim of this paper is to summarise the peer-reviewed reports of M&E in this sector and identify the key issues which need to be addressed in ensuring that such evaluations provide useful information on the work of these organisations.A rigorous evidence base for designing future interventions will provide an opportunity for enhancing the effectiveness of working equid NGO operations. Increased availability of M&E reports in the peer-reviewed literature will enable NGOs to learn from one another and disseminate to a wider audience information on the role of working Equidae and the issues they face.     

Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing

Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.     

Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios

Even though human and chimpanzee gene sequences are nearly 99% identical, sequence comparisons can nevertheless be highly informative in identifying biologically important changes that have occurred since our ancestral lineages diverged. We analyzed alignments of 7645 chimpanzee gene sequences to their human and mouse orthologs. These three-species sequence alignments allowed us to identify genes undergoing natural selection along the human and chimp lineage by fitting models that include parameters specifying rates of synonymous and nonsynonymous nucleotide substitution. This evolutionary approach revealed an informative set of genes with significantly different patterns of substitution on the human lineage compared with the chimpanzee and mouse lineages. Partitions of genes into inferred biological classes identified accelerated evolution in several functional classes, including olfaction and nuclear transport. In addition to suggesting adaptive physiological differences between chimps and humans, human-accelerated genes are significantly more likely to underlie major known Mendelian disorders.     

Local selection and latitudinal variation in a marine predator-prey interaction

Although pairs of species often interact over broad geographic ranges, few studies have explored how interactions vary across these large spatial scales. Surveys along 1500 kilometers of the Pacific coast of North America documented marked variation in the frequency of predation by the snail Nucella canaliculata on the intertidal mussel Mytilus californianus. Laboratory rearing experiments suggest that regional differences in drilling behavior have a genetic basis, and mitochondrial sequence variation confirms that gene flow is low among these snail populations. Marine communities separated by hundreds of kilometers may have intrinsically different dynamics, with interactions shaped by restricted gene flow and spatially varying selection.     

Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle

In striated muscle, the plasma membrane forms tubular invaginations (transverse tubules or T-tubules) that function in depolarization-contraction coupling. Caveolin-3 and amphiphysin were implicated in their biogenesis. Amphiphysin isoforms have a putative role in membrane deformation at endocytic sites. An isoform of amphiphysin 2 concentrated at T-tubules induced tubular plasma membrane invaginations when expressed in nonmuscle cells. This property required exon 10, a phosphoinositide-binding module. In developing myotubes, amphiphysin 2 and caveolin-3 segregated in tubular and vesicular portions of the T-tubule system, respectively. These findings support a role of the bilayer-deforming properties of amphiphysin at T-tubules and, more generally, a physiological role of amphiphysin in membrane deformation.     

CRISPR provides acquired resistance against viruses in prokaryotes

Clustered regularly interspaced short palindromic repeats (CRISPR) are a distinctive feature of the genomes of most Bacteria and Archaea and are thought to be involved in resistance to bacteriophages. We found that, after viral challenge, bacteria integrated new spacers derived from phage genomic sequences. Removal or addition of particular spacers modified the phage-resistance phenotype of the cell. Thus, CRISPR, together with associated cas genes, provided resistance against phages, and resistance specificity is determined by spacer-phage sequence similarity.