Endothelialization of sirolimus-eluting stents with slow and extended drug release in the porcine overstretch model

BACKGROUND: Vascular healing of intracoronary stents has been shown to be delayed in drug-eluting stents (DES) due to the cytotoxic compounds on the stent surface that prevent stent ingrowth and endothelialization. The lack of endothelialization explains the occurrence of late and very late stent thrombosis in DES. MATERIALS AND METHODS: In 11 house swines (body weight 38-45 kg), 3 stents were implanted randomly into the 3 large epicardial coronary arteries, namely a bare-metal stent (BMS), a sirolimus-eluting stent with slow-release (SES) and a SES with extended-release (SESXR). Stent length was 18 mm, and stent diameter 3 mm. All stents were of identical design. Animals were followed for 3 (n = 3), 7 (n = 4) and 14 (n = 4) days, respectively. One animal died before implantation due to hyperthermia. On the day of explantation, the animals were euthanized and endothelialization was tested by scanning electron microscopy after drying and sputtering the samples. Endothelial coverage was determined semiquantitatively by 2 observers. RESULTS: Endothelialization was more rapid with BMS and SESXR than SES at 3 and 14 days. At 7 days there were no significant differences between the 2 SES. CONCLUSIONS: Endothelialization of intracoronary stents is faster with BMS and SESXR at 3 days than with SES. These differences persist at 14 days, suggesting delayed vascular healing with the slow-release SES.

Inhibition of L-type amino acid transport with non-physiological amino acids in the Pahenu2 mouse model of phenylketonuria

Phenylketonuria, an autosomal recessive Mendelian disorder, is one of the most common inborn errors of metabolism. Although currently treated by diet, many suboptimal outcomes occur for patients. Neuropathological outcomes include cognitive loss, white matter abnormalities, and hypo- or demyelination, resulting from high concentrations and/or fluctuating levels of phenylalanine. High phenylalanine can also result in competitive exclusion of other large neutral amino acids from the brain, including tyrosine and tryptophan (essential precursors of dopamine and serotonin). This competition occurs at the blood brain barrier, where the L-type amino acid transporter, LAT1, selectively facilitates entry of large neutral amino acids. The hypothesis of these studies is that certain non-physiological amino acids (NPAA; DL-norleucine (NL), 2-aminonorbornane (NB; 2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid), α-aminoisobutyrate (AIB), and α-methyl-aminoisobutyrate (MAIB)) would competitively inhibit LAT1 transport of phenylalanine (Phe) at the blood-brain barrier interface. To test this hypothesis, Pah-/- mice (n=5, mixed gender; Pah+/-(n=5) as controls) were fed either 5% NL, 0.5% NB, 5% AIB or 3% MAIB (w/w 18% protein mouse chow) for 3 weeks. Outcome measurements included food intake, body weight, brain LNAAs, and brain monoamines measured via LCMS/MS or HPLC. Brain Phe values at sacrifice were significantly reduced for NL, NB, and MAIB, verifying the hypothesis that these NPAAs could inhibit Phe trafficking into the brain. However, concomitant reductions in tyrosine and methionine occurred at the concentrations employed. Blood Phe levels were not altered indicating no effect of NPAA competitors in the gut. Brain NL and NB levels, measured with HPLC, verified both uptake and transport of NPAAs. Although believed predominantly unmetabolized, NL feeding significantly increased blood urea nitrogen. Pah-/-disturbances of monoamine metabolism were exacerbated by NPAA intervention, primarily with NB (the prototypical LAT inhibitor). To achieve the overarching goal of using NPAAs to stabilize Phe transport levels into the brain, a specific Phe-reducing combination and concentration of NPAAs must be found. Our studies represent the first in vivo use of NL, NB and MAIB in Pah-/- mice, and provide proof-of-principle for further characterization of these LAT inhibitors. Our data is the first to document an effect of MAIB, a specific system A transport inhibitor, on large neutral amino acid transport.

Effects of EDP-420 on penicillin-resistant and quinolone- and penicillin-resistant pneumococci in the rabbit meningitis model

OBJECTIVES: To test the efficacy of EDP-420, a new ketolide, in experimental pneumococcal meningitis and to determine its penetration into the CSF. METHODS: The experimental rabbit model was used in this study and EDP-420 was tested against a penicillin-resistant and a penicillin- and quinolone-resistant mutant. EDP-420 was also tested against both strains in time-killing assays over 8 h in vitro. RESULTS: In experimental meningitis, EDP-420 produced a bactericidal activity comparable to the standard regimen based on a combination of vancomycin with ceftriaxone against a penicillin-resistant Streptococcus pneumoniae and a penicillin- and quinolone-resistant S. pneumoniae isolate. The penetration of EDP-420 into inflamed meninges was 38% after an i.v. injection of 10 mg/kg. The bactericidal activity of EDP-420 was also confirmed in in vitro time-killing assays. CONCLUSIONS: EDP-420 is an efficacious alternative treatment in pneumococcal meningitis, especially when resistant strains are suspected.

Statistical inference for the optimal approximating model

In the setting of high-dimensional linear models with Gaussian noise, we investigate the possibility of confidence statements connected to model selection. Although there exist numerous procedures for adaptive (point) estimation, the construction of adaptive confidence regions is severely limited (cf. Li in Ann Stat 17:1001–1008, 1989). The present paper sheds new light on this gap. We develop exact and adaptive confidence regions for the best approximating model in terms of risk. One of our constructions is based on a multiscale procedure and a particular coupling argument. Utilizing exponential inequalities for noncentral χ2-distributions, we show that the risk and quadratic loss of all models within our confidence region are uniformly bounded by the minimal risk times a factor close to one.

Topological lattice actions for the 2d XY model

We consider the 2d XY Model with topological lattice actions, which are invariant against small deformations of the field configuration. These actions constrain the angle between neighbouring spins by an upper bound, or they explicitly suppress vortices (and anti-vortices). Although topological actions do not have a classical limit, they still lead to the universal behaviour of the Berezinskii-Kosterlitz-Thouless (BKT) phase transition — at least up to moderate vortex suppression. In the massive phase, the analytically known Step Scaling Function (SSF) is reproduced in numerical simulations. However, deviations from the expected universal behaviour of the lattice artifacts are observed. In the massless phase, the BKT value of the critical exponent ηc is confirmed. Hence, even though for some topological actions vortices cost zero energy, they still drive the standard BKT transition. In addition we identify a vortex-free transition point, which deviates from the BKT behaviour.

Use of a Th1 Stimulator Adjuvant for Vaccination against Neospora caninum Infection in the Pregnant Mouse Model

Vertical transmission from an infected cow to its fetus accounts for the vast majority of new Neospora caninum infections in cattle. A vaccine composed of a chimeric antigen named recNcMIC3-1-R, based on predicted immunogenic domains of the two microneme proteins NcMIC1 and NcMIC3, the rhoptry protein NcROP2, and emulsified in saponin adjuvants, significantly reduced the cerebral infection in non-pregnant BALB/c mice. Protection was associated with a mixed Th1/Th2-type cytokine response. However, the same vaccine formulation elicited a Th2-type immune response in pregnant mice and did not prevent vertical transmission or disease, neither in dams nor in offspring mice. In this study, an alternative vaccine formulation containing recNcMIC3-1-R emulsified in Freund’s incomplete adjuvant, a stimulator of the cellular immunity, was investigated. No protection against vertical transmission and cerebral infection in the pregnant mice and a very limited protective effect in the non-pregnant mice were observed. The vaccine induced a Th1-type immune response characterized by high IgG2a titres and strong IFN-γ expression, which appeared detrimental to pregnancy.

Construct Validity of the Pig Intestine Model in the Simulation of Laparoscopic Urethrovesical Anastomosis

Introduction: Laparoscopic training models are increasingly important in urology to allow trainees to improve their laparoscopic skills prior to going to the operating room. For a training model to be valid, it must correlate with performance in a real case. The model must also discriminate between experienced and inexperienced subjects. [See PDF for complete abstract]

Molecular basis of Corynebacterium diphtheriae virulence and infection in the Caenorhabditis elegans model host

Corynebacterium diphtheriae is the causative agent of cutaneous and pharyngeal diphtheria in humans. While lethality is certainly caused by diphtheria toxin, corynebacterial colonization may primarily require proteinaceous fibers called pili, which mediate adherence to specific tissues. The type strain of C. diphtheriae possesses three distinct pilus structures, namely the SpaA, SpaD, and SpaH-type pili, which are encoded by three distinct pilus gene clusters. The pilus is assembled onto the bacterial peptidoglycan by a specific transpeptidase enzyme called sortase. Although the SpaA pili are shown to be specific for pharyngeal cells in vitro, little is known about functions of the three pili in bacterial pathogenesis. This is mainly due to lack of in vivo models of corynebacterial infection. As an alternative to mouse models as mice do not have functional receptors for diphtheria toxin, in this study I use Caenorhabditis elegans as a model host for C. diphtheriae. A simple C. elegans model would be beneficial in determining the specific role of each pilus-type and the literature suggests that C. elegans infection model can be used to study a variety of bacterial species giving insight into bacterial virulence and host-pathogen interactions. My study examines the hypothesis that pili and toxin are major virulent determinants of C. diphtheriae in the C. elegans model host.

Genetic analysis of tumor progression susceptibility in the mouse skin model

In the field of chemical carcinogenesis the use of animal models has proved to be a useful tool in dissecting the multistage process of tumor formation. In this regard the outbred SENCAR mouse has been the strain of choice in the analysis of skin carcinogenesis given its high sensitivity to the chemically induced acquisition of premalignant lesions, papillomas, and the later progression of these lesions into squamous cell carcinomas (SCC).^ The derivation of an inbred strain from the SENCAR stock called SSIN, that in spite of a high sensitivity to the development of papillomas lack the ability to transform these premalignant lesions into SCC, suggested that tumor promotion and progression were under the genetic control of different sets of genes.^ In the present study the nature of susceptibility to tumor progression was investigated. Analysis of F1 hybrids between the outbred SENCAR and SSIN mice suggested that there is at least one dominant gene responsible for susceptibility to tumor progression.^ Later development of another inbred strain from the outbred SENCAR stock, that had sensitivity to both tumor promotion and progression, allowed the formulation of a more accurate genetic model. Using this newly derived line, SENCAR B/Pt. and SSIN it was determined that there is one dominant tumor progression susceptibility gene. Linkage analysis showed that this gene maps to mouse chromosome 14 and it was possible to narrow the region to a 16 cM interval.^ In order to better characterize the nature of the progression susceptibility differences between these two strains, their proliferative pattern was investigated. It was found that SENCAR B/Pt, have an enlarged proliferative compartment with overexpression of cyclin D1, p16 and p21. Further studies showed an aberrant overexpression of TGF-$\beta$ in the susceptible strain, an increase in apoptosis, p53 protein accumulation and early loss of connexin 26. These results taken together suggest that papillomas in the SENCAR B/Pt. mice have higher proliferation and may have an increase in genomic instability, these two factors would contribute to a higher sensitivity to tumor progression. ^

The coupled atmosphere–chemistry–ocean model SOCOL-MPIOM

The newly developed atmosphere–ocean-chemistry-climate model SOCOL-MPIOM is presented by demonstrating the influence of the interactive chemistry module on the climate state and the variability. Therefore, we compare pre-industrial control simulations with (CHEM) and without (NOCHEM) interactive chemistry. In general, the influence of the chemistry on the mean state and the variability is small and mainly restricted to the stratosphere and mesosphere. The largest differences are found for the atmospheric dynamics in the polar regions, with slightly stronger northern and southern winter polar vortices in CHEM. The strengthening of the vortex is related to larger stratospheric temperature gradients, which are attributed to a parametrization of the absorption of ozone and oxygen in the Lyman-alpha, Schumann–Runge, Hartley, and Higgins bands. This effect is parametrized in the version with interactive chemistry only. A second reason for the temperature differences between CHEM and NOCHEM is related to diurnal variations in the ozone concentrations in the higher atmosphere, which are missing in NOCHEM. Furthermore, stratospheric water vapour concentrations differ substantially between the two experiments, but their effect on the temperatures is small. In both setups, the simulated intensity and variability of the northern polar vortex is inside the range of present day observations. Sudden stratospheric warming events are well reproduced in terms of their frequency, but the distribution amongst the winter months is too uniform. Additionally, the performance of SOCOL-MPIOM under changing external forcings is assessed for the period 1600–2000 using an ensemble of simulations driven by a spectral solar forcing reconstruction. The amplitude of the reconstruction is large in comparison to other state-of-the-art reconstructions, providing an upper limit for the importance of the solar signal. In the pre-industrial period (1600–1850) the simulated surface temperature trends are in reasonable agreement with temperature reconstructions, although the multi-decadal variability is more pronounced. This enhanced variability can be attributed to the variability in the solar forcing. The simulated temperature reductions during the Maunder Minimum are in the lowest probability range of the proxy records. During the Dalton Minimum, when also volcanic forcing is an important driver of temperature variations, the agreement is better. In the industrial period from 1850 onward SOCOL-MPIOM overestimates the temperature increase in comparison to observational data sets. Sensitivity simulations show that this overestimation can be attributed to the increasing trend in the solar forcing reconstruction that is used in this study and an additional warming induced by the simulated ozone changes.

The career resources model: An integrative framework for career counsellors

Changes in the nature of work and organizations have led to an increased need for self-directed career management (SDCM). However, there is no consensus in the literature of what constitutes SDCM and many related concepts have been proposed. Integrating previous research across different conceptualizations of SDCM, the paper proposes four critical career resources which are essential for career development in the modern context: human capital resources, social resources, psychological resources, and identity resources. Implications of this framework for counselling practice are presented.