Cardiovascular, respiratory, gastrointestinal and behavioral effects of intravenous lidocaine in healthy, conscious horses and evaluation of the relationship with lidocaine and monoethylglycinexylidide serum concentrations

This study aimed to evaluate the relationship between the serum concentrations of lidocaine/ monoethylglycinexylidide (MEGX) and their effects on several systems in horses. Five healthy, conscious horses received a two-hour placebo intravenous infusion followed by a two-hour lidocaine infusion (bolus of 1.3 mg/kg over ten minutes followed by a continuous rate infusion of 0.05 mg/kg/min). Lidocaine and MEGX serum concentrations were sampled every ten to fifteen minutes during the experiment, and the presence of muscle fasciculations and loss of balance as well as the respiratory, digestive and cardiovascular systems of the five horses were evaluated by means of different non-invasive methods. During the lidocaine infusion, the mean (f SD) lidocaine and MEGX concentrations were respectively 768.88 +/- 93.32ng/ml and 163.08 +/- 108.98 ng/ml. The infusion of lidocaine significantly influenced the presence of fasciculations, caused a statistically but non-clinically significant decrease of systolic and diastolic blood pressures, which were both correlated with lidocaine and MEGX serum concentrations, and it increased the duodenal contractions frequency, which was correlated with the serum lidocaine concentration. In this study, mild hypotensive and prokinetic effects of short-term lidocaine infusion were observed

Dairy herd mastitis and reproduction: using simulation to aid interpretation of results from discrete time survival analysis

Probabilistic sensitivity analysis (PSA) is a simulation-based technique for evaluating the relative importance of different inputs to a complex process model. It is commonly employed in decision analysis and for evaluation of the potential impact of uncertainty in research findings on clinical practice, but has a wide variety of other possible applications. In this example, it was used to evaluate the association between herd-level udder health and reproductive performance in dairy herds. Although several recent studies have found relatively large associations between mastitis and fertility at the level of individual inseminations or lactations, the current study demonstrated that herd-level intramammary infection status is highly unlikely to have a clinically significant impact on the overall reproductive performance of a dairy herd under typical conditions. For example, a large increase in incidence rate of clinical mastitis (from 92 to 131 cases per 100 cows per year) would be expected to increase a herd's modified FERTEX score (a cost-based measure of overall reproductive performance) by just £4.501 per cow per year. The herd's background level of submission rate (proportion of eligible cows served every 21 days) and pregnancy risk (proportion of inseminations leading to a pregnancy) correlated strongly with overall reproductive performance and explained a large proportion of the between-herd variation in performance. PSA proved to be a highly useful technique to aid understanding of results from a complex statistical model, and has great potential for a wide variety of applications within the field of veterinary science

Genetic parameters for somatic cell score according to udder infection status in Valle del Belice dairy sheep and impact of imperfect diagnosis of infection

<p>Abstract</p> <p>Background</p> <p>Somatic cell score (SCS) has been promoted as a selection criterion to improve mastitis resistance. However, SCS from healthy and infected animals may be considered as separate traits. Moreover, imperfect sensitivity and specificity could influence animals' classification and impact on estimated variance components. This study was aimed at: (1) estimating the heritability of bacteria negative SCS, bacteria positive SCS, and infection status, (2) estimating phenotypic and genetic correlations between bacteria negative and bacteria positive SCS, and the genetic correlation between bacteria negative SCS and infection status, and (3) evaluating the impact of imperfect diagnosis of infection on variance component estimates.</p> <p>Methods</p> <p>Data on SCS and udder infection status for 1,120 ewes were collected from four Valle del Belice flocks. The pedigree file included 1,603 animals. The SCS dataset was split according to whether animals were infected or not at the time of sampling. A repeatability test-day animal model was used to estimate genetic parameters for SCS traits and the heritability of infection status. The genetic correlation between bacteria negative SCS and infection status was estimated using an MCMC threshold model, implemented by Gibbs Sampling.</p> <p>Results</p> <p>The heritability was 0.10 for bacteria negative SCS, 0.03 for bacteria positive SCS, and 0.09 for infection status, on the liability scale. The genetic correlation between bacteria negative and bacteria positive SCS was 0.62, suggesting that they may be genetically different traits. The genetic correlation between bacteria negative SCS and infection status was 0.51. We demonstrate that imperfect diagnosis of infection leads to underestimation of differences between bacteria negative and bacteria positive SCS, and we derive formulae to predict impacts on estimated genetic parameters.</p> <p>Conclusions</p> <p>The results suggest that bacteria negative and bacteria positive SCS are genetically different traits. A positive genetic correlation between bacteria negative SCS and liability to infection was found, suggesting that the approach of selecting animals for decreased SCS should help to reduce mastitis prevalence. However, the results show that imperfect diagnosis of infection has an impact on estimated genetic parameters, which may reduce the efficiency of selection strategies aiming at distinguishing between bacteria negative and bacteria positive SCS.</p

Bistability and Bacterial Infections

Bacterial infections occur when the natural host defenses are overwhelmed by invading bacteria. The main component of the host defense is impaired when neutrophil count or function is too low, putting the host at great risk of developing an acute infection. In people with intact immune systems, neutrophil count increases during bacterial infection. However, there are two important clinical cases in which they remain constant: a) in patients with neutropenic-associated conditions, such as those undergoing chemotherapy at the nadir (the minimum clinically observable neutrophil level); b) in ex vivo examination of the patient's neutrophil bactericidal activity. Here we study bacterial population dynamics under fixed neutrophil levels by mathematical modelling. We show that under reasonable biological assumptions, there are only two possible scenarios: 1) Bacterial behavior is monostable: it always converges to a stable equilibrium of bacterial concentration which only depends, in a gradual manner, on the neutrophil level (and not on the initial bacterial level). We call such a behavior type I dynamics. 2) The bacterial dynamics is bistable for some range of neutrophil levels. We call such a behavior type II dynamics. In the bistable case (type II), one equilibrium corresponds to a healthy state whereas the other corresponds to a fulminant bacterial infection. We demonstrate that published data of in vitro Staphylococcus epidermidis bactericidal experiments are inconsistent with both the type I dynamics and the commonly used linear model and are consistent with type II dynamics. We argue that type II dynamics is a plausible mechanism for the development of a fulminant infection

The Glyceraldehyde-3-Phosphate Dehydrogenase and the Small GTPase Rab 2 Are Crucial for Brucella Replication

The intracellular pathogen Brucella abortus survives and replicates inside host cells within an endoplasmic reticulum (ER)-derived replicative organelle named the “Brucella-containing vacuole” (BCV). Here, we developed a subcellular fractionation method to isolate BCVs and characterize for the first time the protein composition of its replicative niche. After identification of BCV membrane proteins by 2 dimensional (2D) gel electrophoresis and mass spectrometry, we focused on two eukaryotic proteins: the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the small GTPase Rab 2 recruited to the vacuolar membrane of Brucella. These proteins were previously described to localize on vesicular and tubular clusters (VTC) and to regulate the VTC membrane traffic between the endoplasmic reticulum (ER) and the Golgi. Inhibition of either GAPDH or Rab 2 expression by small interfering RNA strongly inhibited B. abortus replication. Consistent with this result, inhibition of other partners of GAPDH and Rab 2, such as COPI and PKC ι, reduced B. abortus replication. Furthermore, blockage of Rab 2 GTPase in a GDP-locked form also inhibited B. abortus replication. Bacteria did not fuse with the ER and instead remained in lysosomal-associated membrane vacuoles. These results reveal an essential role for GAPDH and the small GTPase Rab 2 in B. abortus virulence within host cells

Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis.

ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) constitute a family of endopeptidases related to matrix metalloproteinases. These proteases have been largely implicated in tissue remodeling and angiogenesis associated with physiological and pathological processes. To elucidate the in vivo functions of ADAMTS-12, we have generated a knockout mouse strain (Adamts12−/−) in which Adamts12 gene was deleted. The mutant mice had normal gestations and no apparent defects in growth, life span and fertility. By applying three different in vivo models of angiogenesis (malignant keratinocyte transplantation, Matrigel plug and aortic ring assays) to Adamts12−/− mice, we provide evidence for a protective effect of this host enzyme toward angiogenesis and cancer progression. In the absence of Adamts-12, both the angiogenic response and tumor invasion into host tissue were increased. Complementing results were obtained by using medium conditioned by cells overexpressing human ADAMTS-12, which inhibited vessel outgrowth in the aortic ring assay. This angioinhibitory effect of ADAMTS-12 was independent of its enzymatic activity as a mutated inactive form of the enzyme was similarly efficient in inhibiting endothelial cell sprouting in the aortic ring assay than the wild-type form. Altogether, our results show that ADAMTS-12 displays antiangiogenic properties and protect the host toward tumor progression