Vaccination with the recombinant chimeric antigen recNcMIC3-1-R induces a non-protective Th2-type immune response in the pregnant mouse model for N. caninum infection

The major route of transmission of Neospora caninum in cattle is transplacentally from an infected cow to its progeny. Therefore, a vaccine should be able to prevent both the horizontal transmission from contaminated food or water and the vertical transmission. We have previously shown that a chimeric vaccine composed of predicted immunogenic epitopes of NcMIC3, NcMIC1 and NcROP2 (recNcMIC3-1-R) significantly reduced the cerebral infection in BALB/c mice. In this study, mice were first vaccinated, then mated and pregnant mice were challenged with 2×10(6)N. caninum tachyzoites at day 7-9 of pregnancy. Partial protection was only observed in the mice vaccinated with a tachyzoite crude protein extract but no protection against vertical transmission or cerebral infection in the dams was observed in the group vaccinated with recNcMIC3-1-R. Serological and cytokine analysis showed an overall lower cytokine level in sera associated with a dominant IL-4 expression and high IgG1 titers. Thus, the Th2-type immune response observed in the pregnant mice was not protective against experimental neosporosis, in contrary to the mixed Th1-/Th2-type immune response observed in the non-pregnant mouse model. These results demonstrate that the immunomodulation that occurs during pregnancy was not favorable for the protection against N. caninum infection conferred by vaccination with recNcMIC3-1-R.

Regenerative capacity of individual liver lobes in the microsurgical mouse model

In the development of microsurgical mouse models of hepatic regeneration and repair, lobe-specific regenerative responses were observed. We therefore determined the hepatic regenerative capacity of individual mouse liver lobes. In mice, 26, 60, 75, and 83% of total liver mass was resected. Bromo-deoxyuridine (BrdU) was injected prior to liver harvest and the BrdU labeling index determined in all remaining individual liver lobes. BrdU-positive nuclei were seen in all liver lobes after the 26 and 60% resection, but significantly fewer were detected in the caudate lobe. In the 75% group, equally distributed positive nuclei were found. However, BrdU labeling was scant in the 83% group. In microsurgical mouse liver-regeneration models, the average hepatic response depends on amount of liver tissue resected and on the remaining liver lobe. BrdU incorporation can vary significantly among individual lobes. The lobe-specific differences observed may prove valuable in further investigations of hepatic regeneration and repair.

The well-being model: a new drug interaction model for positive and negative effects

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.

Efficient and Ad Hoc Estimation in the Bivariate Censoring Model

A large number of proposals for estimating the bivariate survival function under random censoring has been made. In this paper we discuss nonparametric maximum likelihood estimation and the bivariate Kaplan-Meier estimator of Dabrowska. We show how these estimators are computed, present their intuitive background and compare their practical performance under different levels of dependence and censoring, based on extensive simulation results, which leads to a practical advise.

A Note on the Asymptotic Variance of Survival Function in the Semi-Markov Model

In Malani and Neilsen (1992) we have proposed alternative estimates of survival function (for time to disease) using a simple marker that describes time to some intermediate stage in a disease process. In this paper we derive the asymptotic variance of one such proposed estimator using two different methods and compare terms of order 1/n when there is no censoring. In the absence of censoring the asymptotic variance obtained using the Greenwood type approach converges to exact variance up to terms involving 1/n. But the asymptotic variance obtained using the theory of the counting process and results from Voelkel and Crowley (1984) on semi-Markov processes has a different term of order 1/n. It is not clear to us at this point why the variance formulae using the latter approach give different results.

Posterior Simulation in the Generalized Linear Model with Semiparmetric Random Effects

Generalized linear mixed models with semiparametric random effects are useful in a wide variety of Bayesian applications. When the random effects arise from a mixture of Dirichlet process (MDP) model, normal base measures and Gibbs sampling procedures based on the Pólya urn scheme are often used to simulate posterior draws. These algorithms are applicable in the conjugate case when (for a normal base measure) the likelihood is normal. In the non-conjugate case, the algorithms proposed by MacEachern and Müller (1998) and Neal (2000) are often applied to generate posterior samples. Some common problems associated with simulation algorithms for non-conjugate MDP models include convergence and mixing difficulties. This paper proposes an algorithm based on the Pólya urn scheme that extends the Gibbs sampling algorithms to non-conjugate models with normal base measures and exponential family likelihoods. The algorithm proceeds by making Laplace approximations to the likelihood function, thereby reducing the procedure to that of conjugate normal MDP models. To ensure the validity of the stationary distribution in the non-conjugate case, the proposals are accepted or rejected by a Metropolis-Hastings step. In the special case where the data are normally distributed, the algorithm is identical to the Gibbs sampler.

Gentamicin increases the efficacy of vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model

In experimental meningitis a single dose of gentamicin (10 mg/kg of body weight) led to gentamicin levels in around cerebrospinal fluid (CSF) of 4 mg/liter for 4 h, decreasing slowly to 2 mg/liter 4 h later. The CSF penetration of gentamicin ranged around 27%, calculated by comparison of areas under the curve (AUC in serum/AUC in CSF). Gentamicin monotherapy (-1.24 log(10) CFU/ml) was inferior to vancomycin monotherapy (-2.54 log(10) CFU/ml) over 8 h against penicillin-resistant pneumococci. However, the combination of vancomycin with gentamicin was significantly superior (-4.48 log(10) CFU/ml) compared to either monotherapy alone. The synergistic activity of vancomycin combined with gentamicin was also demonstrated in vitro in time-kill assays.

Linezolid against penicillin-sensitive and -resistant pneumococci in the rabbit meningitis model

Linezolid, a new oxazolidinone antibiotic, showed good penetration (38+/-4%) into the meninges of rabbits with levels in the CSF ranging from 9.5 to 1.8 mg/L after two i.v. injections (20 mg/kg). Linezolid was clearly less effective than ceftriaxone against a penicillin-sensitive pneumococcal strain. Against a penicillin-resistant strain, linezolid had slightly inferior killing rates compared with the standard regimen (ceftriaxone combined with vancomycin). In vitro, linezolid was marginally bactericidal at concentrations above the MIC (5 x and 10 x MIC).

Grepafloxacin against penicillin-resistant pneumococci in the rabbit meningitis model

Grepafloxacin, a new fluoroquinolone, produced bactericidal activity comparable to that of vancomycin and ceftriaxone in the treatment in rabbits of meningitis caused by a pneumococcal strain highly resistant to penicillin (MIC 4 mg/L) (triangle uplog(10) cfu/mL*h for grepafloxacin, -0.32 +/- 0.15; dose, 15 mg/kg iv; triangle uplog(10) cfu/mL*h for vancomycin, -0.39 +/- 0.18; dose, 2 x 20 mg/kg iv; triangle uplog(10) cfu/mL*h for ceftriaxone, -0.32 +/- 0. 12; dose, 125 mg/kg iv). Higher doses of grepafloxacin (30 mg/kg and 2 x 50 mg/kg) did not improve the killing rates. The combination of grepafloxacin with vancomycin was not significantly superior to monotherapies (P > 0.05). In vitro, grepafloxacin was bactericidal at concentrations above the MIC. Using concentrations around the MIC, addition of vancomycin to grepafloxacin showed synergic activity.

Synergy between trovafloxacin and ceftriaxone against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro

The bactericidal activities of monotherapy with trovafloxacin (-0.37 +/- 0.15 Delta log(10) CFU/ml. h), vancomycin (-0.32 +/- 0.12 Delta log(10) CFU/ml. h), and ceftriaxone (-0.36 +/- 0.19 Delta log(10) CFU/ml. h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar. The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (-0.67 +/- 0.16 Delta log(10) CFU/ml. h) and was slightly superior to ceftriaxone with vancomycin (killing rate, -0.53 +/- 0. 22 Delta log(10) CFU/ml. h), the regimen most commonly used in clinical practice. In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.

Evaluation of cefepime alone and in combination with vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model and in vitro

Cefepime, a broad-spectrum, fourth-generation cephalosporin, showed excellent CSF penetration with levels ranging between 10 and 16 mg/L after two intravenous injections (100 mg/kg). The bactericidal activity of cefepime (-0.60 +/- 0.28 Deltalog(10) cfu/mL/h) was superior to that of ceftriaxone (-0.34 +/- 0.23 Deltalog(10) cfu/mL/h, P < 0.05) and vancomycin (-0.39 +/- 0.19 Deltalog(10) cfu/mL/h, P < 0.05) in the treatment of rabbits with meningitis caused by an isolate highly resistant to penicillin (MIC of penicillin G: 4 mg/L). The addition of vancomycin to both cephalosporins did not significantly increase the killing rate compared with monotherapies (P > 0.05). Similar results were obtained in time-killing experiments in vitro.

Trovafloxacin in combination with vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model

Trovafloxacin, a new fluoroquinolone, produced bactericidal activity (-0.33 +/- 0.13 delta log10 CFU/ml.h; intravenously [i.v.] administered dose, 15 mg/kg) comparable to that of vancomycin (-0.39 +/- 0.18 delta log10 CFU/ml.h; i.v. admininistered dose, 20 mg/kg) in the treatment of experimental meningitis in rabbits due to a pneumococcal strain highly resistant to penicillin (MIC of penicillin G, 4 micrograms/ml). The combination of both drugs significantly increased (P < 0.05) the killing rate (-0.60 +/- 0.23 delta log10 CFU/ml.h) compared to that produced by either monotherapy. These results were also confirmed in vitro.