The successful use of a subcutaneous catheter in the management of severe subcutaneous emphysema in a dog with laryngeal crush injury and tracheostomy tube placement.

OBJECTIVE: To describe the placement of a subcutaneous catheter in a dog for the management of severe subcutaneous emphysema secondary to severe laryngeal crushing injury and temporary tracheostomy tube placement. CASE SUMMARY: A 6-year-old male neutered Kelpie suffered a severe laryngeal crushing injury following a dog attack. Case management included the placement of a temporary tracheostomy tube due to severe respiratory compromise and inspiratory dyspnea associated with the crush injury. During hospitalization, the patient developed severe subcutaneous emphysema, pneumomediastinum, and a pneumothorax as a complication of the laryngeal crushing injury and temporary tracheostomy. A subcutaneous catheter was placed to manage the recurrent subcutaneous emphysema while the tracheostomy stoma healed. Five months posttrauma, the dog returned to normal with mild stridor during excitement and while panting. NEW OR UNIQUE INFORMATION PROVIDED: This is the first report in veterinary medicine describing the use of a subcutaneous catheter for the management of subcutaneous emphysema secondary to laryngeal crush injury and temporary tracheostomy tube placement.

Markers of tissue perfusion and their relation to mortality in dogs with blunt trauma.

OBJECTIVE: To evaluate admission Animal Trauma Triage (ATT) score, shock index (SI), and markers of perfusion, including base excess (BE), plasma lactate, and lactate clearance in dogs with blunt trauma. DESIGN: Prospective observational clinical study from 2013 to 2015. SETTING: Private veterinary referral and emergency center. ANIMALS: Forty-four client-owned dogs hospitalized following blunt trauma. INTERVENTION: Within 1 hour of presentation and prior to fluid administration an initial hematocrit, total plasma protein, blood glucose, plasma lactate, blood gas, and electrolytes were obtained for analysis. Plasma lactate concentrations were also measured 4 and 8 hours following initial measurement, and a 4-hour lactate clearance was calculated if patients had an increased admission plasma lactate. ATT score and SI were calculated for each patient based on admission data. Outcome was defined as survival to hospital discharge. MEASUREMENTS AND MAIN RESULTS: Twenty-nine dogs survived, 14 were euthanized, and 1 died. Nonsurviving dogs had a lower mean pH (7.28 ± 0.03 vs 7.36 ± 0.01, P = 0.006), lower median HCO3 (15.7 vs 18.8 mmol/L, P = 0.004), lower median admission BE (-11.0 vs -7.0 mmol/L, P = 0.004), and higher median admission lactate (3.1 vs 2.4 mmol/L, P = 0.036) than those who survived. Median ATT was significantly higher in nonsurvivors (5 vsF 2, P < 0.001). The SI was not significantly different between survivors and nonsurvivors (P = 0.41). There was no difference in median 4-hour lactate (P = 0.34), median 8-hour lactate (P = 0.19), or 4-hour lactate clearance (P = 0.83) in survivors compared to nonsurvivors. No other statistically significant differences were noted between groups. CONCLUSION: Dogs hospitalized following blunt trauma with a lower admission pH, HCO3 , and BE and a higher admission plasma lactate were less likely to survive to hospital discharge. Median ATT score was also significantly higher in nonsurvivors. Although lactate clearance was not predictive of survival, the sample size was small, and additional studies with a larger study population are warranted.

Successful management and recovery of a dog with immune-mediated thrombocytopenia following vincristine overdose.

OBJECTIVE: To describe the management and outcome of a dog following a 10-fold dosing error of vincristine. CASE SUMMARY: A 2-year-old neutered female Toy Fox Terrier presenting for immune-mediated thrombocytopenia was administered an accidental overdose of vincristine (0.2 mg/kg [2.71 mg/m2 ]). The dog was managed for severe gastrointestinal signs, neutropenia, and neurological consequences secondary to the overdose. Neurological signs included diffuse muscle tremors, limb hyperextension, and myalgia during the dog's hospitalization. Medical management consisted of aggressive supportive care in addition to novel strategies, including folinic acid, glutamic acid, and Tbo-filgrastim. The dog was discharged from the hospital after 12 days of hospitalization and recovered completely within a month of the overdose with no lasting consequences. NEW OR UNIQUE INFORMATION PROVIDED: This is the first report of the successful management of severe vincristine overdose in a dog. Therapy included the use of Tbo-filgrastim, folinic acid, and glutamic acid along with aggressive supportive care.

Species ecology explains the spatial components of genetic diversity in tropical reef fishes.

Generating genomic data for 19 tropical reef fish species of the Western Indian Ocean, we investigate how species ecology influences genetic diversity patterns from local to regional scales. We distinguish between the α, ß and γ components of genetic diversity, which we subsequently link to six ecological traits. We find that the α and γ components of genetic diversity are strongly correlated so that species with a high total regional genetic diversity display systematically high local diversity. The α and γ diversity components are negatively associated with species abundance recorded using underwater visual surveys and positively associated with body size. Pelagic larval duration is found to be negatively related to genetic ß diversity supporting its role as a dispersal trait in marine fishes. Deviation from the neutral theory of molecular evolution motivates further effort to understand the processes shaping genetic diversity and ultimately the diversification of the exceptional diversity of tropical reef fishes.

Microbial embryonal colonization during pipefish male pregnancy.

While originally acquired from the environment, a fraction of the microbiota is transferred from parents to offspring. The immune system shapes the microbial colonization, while commensal microbes may boost host immune defences. Parental transfer of microbes in viviparous animals remains ambiguous, as the two transfer routes (transovarial vs. pregnancy) are intermingled within the maternal body. Pipefishes and seahorses (syngnathids) are ideally suited to disentangle transovarial microbial transfer from a contribution during pregnancy due to their maternal egg production and their unique male pregnancy. We assessed the persistency and the changes in the microbial communities of the maternal and paternal reproductive tracts over proceeding male pregnancy by sequencing microbial 16S rRNA genes of swabs from maternal gonads and brood pouches of non-pregnant and pregnant fathers. Applying parental immunological activation with heat-killed bacteria, we evaluated the impact of parental immunological status on microbial development. Our data indicate that maternal gonads and paternal brood pouches harbor distinct microbial communities, which could affect embryonal development in a sex-specific manner. Upon activation of the immune system, a shift of the microbial community was observed. The activation of the immune system induced the expansion of microbiota richness during late pregnancy, which corresponds to the time point of larval mouth opening, when initial microbial colonization must take place.

Selection by higher-order effects of salinity and bacteria on early life-stages of Western Baltic spring-spawning herring.

Habitat stratification by abiotic and biotic factors initiates divergence of populations and leads to ecological speciation. In contrast to fully marine waters, the Baltic Sea is stratified by a salinity gradient that strongly affects fish physiology, distribution, diversity and virulence of important marine pathogens. Animals thus face the challenge to simultaneously adapt to the concurrent salinity and cope with the selection imposed by the changing pathogenic virulence. Western Baltic spring-spawning herring (Clupea harengus) migrate to spawning grounds characterized by different salinities to which herring are supposedly adapted. We hypothesized that herring populations do not only have to cope with different salinity levels but that they are simultaneously exposed to higher-order effects that accompany the shifts in salinity, that is induced pathogenicity of Vibrio bacteria in lower saline waters. To experimentally evaluate this, adults of two populations were caught in their spawning grounds and fully reciprocally crossed within and between populations. Larvae were reared at three salinity levels, representing the spawning ground salinity of each of the two populations, or Atlantic salinity conditions resembling the phylogenetic origin of Clupea harengus. In addition, larvae were exposed to a Vibrio spp. infection. Life-history traits and gene expression analysis served as response variables. Herring seem adapted to Baltic Sea conditions and cope better with low saline waters. However, upon a bacterial infection, herring larvae suffer more when kept at lower salinities implying reduced resistance against Vibrio or higher Vibrio virulence. In the context of recent climate change with less saline marine waters in the Baltic Sea, such interactions may constitute key future stressors.

Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus.

A high-throughput screen based on a viral replication assay was used to identify inhibitors of the human cytomegalovirus. Using this approach, hit compound 1 was identified as a 4 µM inhibitor of HCMV that was specific and selective over other herpes viruses. Time of addition studies indicated compound 1 exerted its antiviral effect early in the viral life cycle. Mechanism of action studies also revealed that this series inhibited infection of MRC-5 and ARPE19 cells by free virus and via direct cell-to-cell spread from infected to uninfected cells. Preliminary structure-activity relationships demonstrated that the potency of compound 1 could be improved to a low nanomolar level, but metabolic stability was a key optimization parameter for this series. A strategy focused on minimizing metabolic hydrolysis of the N1-amide led to an alternative scaffold in this series with improved metabolic stability and good pharmacokinetic parameters in rat.

Hypodermic self-insemination as a reproductive assurance strategy.

Self-fertilization occurs in a broad range of hermaphroditic plants and animals, and is often thought to evolve as a reproductive assurance strategy under ecological conditions that disfavour or prevent outcrossing. Nevertheless,selfing ability is far from ubiquitous among hermaphrodites, and may be constrained in taxa where the male and female gametes of the same individual cannot easily meet. Here, we report an extraordinary selfing mechanism in one such species, the free-living flatworm Macrostomum hystrix. To test the hypothesis that adaptations to hypodermic insemination of the mating partner under outcrossing also facilitate selfing, we experimentally manipulated the social environment of these transparent flatworms and then observed the spatial distribution of received sperm in vivo. We find that this distribution differs radically between conditions allowing or preventing outcrossing, implying that isolated individuals use their needle-like stylet (male copulatory organ) to inject own sperm into their anterior body region, including into their own head, from where they then apparently migrate to the site of (self-)fertilization. Conferring the ability to self could thus be an additional consequence of hypodermic insemination, a widespread fertilization mode that is especially prevalent among simultaneously hermaphroditic animals and probably evolves due to sexual conflict over the transfer and subsequent fate of sperm.

Molecular dynamics simulations and structure-based rational design lead to allosteric HCV NS5B polymerase thumb pocket 2 inhibitor with picomolar cellular replicon potency.

The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC50 = 120 and 110 pM, respectively) and with EC50 ≤ 80 nM against gt 2-6.

Mechanism and regioselectivity of the cycloaddition of thiones derived from Meldrum's acid, malonates, or other dicarbonyls.

Several alpha,alpha-dioxothiones were generated in situ and reacted with 1,3-dienes of varying electronic and steric properties. It was found that thiones 10a and 11a reacted well with electron-rich or electron-poor dienes and are complementary in their regioselectivities when steric effects are at play. The calculated preferred mechanistic pathway implies a thiiranium zwitterion intermediate.