Cerebro-spinal flow pattern in the cervical subarachnoid space of healthy volunteers: Influence of the spinal cord morphology.

Introduction: Toward further cerebro-spinal flow quantification in clinical practice, this study aims at assessing the variations in the cerebro spinal fluid flow pattern associated with change in the morphology of the subarachnoid space of the cervical canal of healthy humans by developing a computational fluid dynamics model.

Methods: 3D T2-space MRI sequence images of the cervical spine were used to segment 11 cervical subarachnoid space. Model validation (time-step, mesh size, size and number of boundary layers, influences of parted inflow and inflow continuous velocity) was performed a 40-year-old patient-specific model.

Assessment of the tolerance angle for pedicle screw insertion.

Cannulation process intervenes before implantation of pedicle screw and depends on the surgeon's experience. A reliable experimental protocol has been developed for the characterization of the slipping behavior of the surgical tool on the cortical shell simulated by synthetic materials. Three types of synthetic foam samples with three different densities were tested using an MTS Acumen 3 A/T electrodynamic device with a tri-axis 3 kN Kistler load cell mounted on a surgical tool, moving at a constant rotational speed of 10° mm and performing a three-step cannulation test.

Sliding on cortical shell: Biomechanical characterization of the vertebral cannulation for pedicle screw insertion.

Background: Pedicular screws pull-out has been well studied unlike their insertion. A need for characterizing cannulation before pedicle screw implantation is highlighted in literature and offers promising prospects for future intra-operation instrumentation. A reliable cannulation protocol for ex-vivo testing in swine and cadaver vertebrae is presented in this work to predict extra pedicular perforation.

Traction mechanical characterization of porcine mitral valve annulus.

The Mitral Annulus (MA) is an anisotropic, fibrous, flexible and dynamical structure. While MA dynamics are well documented, its passive mechanical properties remain poorly investigated to complete the design of adequate prostheses. Mechanical properties in traction on four sections of the MA (aortic, left, posterior and right segments) were assessed using a traction test system with a 30 N load cell and pulling jaws for sample fixation.

RASE: Modeling cumulative disadvantage due to marginalized group status in academia.

We propose a framework of Resources, Achievement, Status, and Events (RASE) that allows the many disparate but well-documented phenomena affecting underrepresented groups in STEM to be assembled into a story of career trajectories, illuminating the possible cumulative impact of many small inequities. Our framework contains a three-component deterministic cycle of (1) production of Achievements from Resources, (2) updated community Status due to Achievements, and (3) accrual of additional Resources based on community Status. A fourth component, stochastic Events, can influence an individual's level of Resources or Achievements at each time step of the cycle.

Home versus indoor trampoline park injuries: A four-year review of hospital admissions, associated costs, and impact on patients.

Hospital admissions for trampoline-related injuries are a metric of injury severity. The literature shows hospital admissions are more likely to occur from trampoline park injuries rather than home trampoline injuries. The purpose of this study was to investigate the demographics, injury characteristics, patient experiences, and economic impact of home versus trampoline park injuries requiring admission to hospital before and after two indoor trampoline parks opened in the catchment area of a Level II trauma centre.

Catfish Bite Case Report.

Although catfish are found worldwide and commonly consumed in the southern United States, fatal infections from catfish are rare. Edwardsiella tarda is a bacterium known to cause gastrointestinal distress most commonly, but extraintestinal infections are a rarely considered danger for those acquiring, preparing, and consuming aquatic animals. Susceptible to all gram-negative active antibiotics, it is easily treated except in immunocompromised hosts, such as those with malignancy, diabetes, and hepatic dysfunction.

Synergistic activity of troxacitabine (Troxatyl) and gemcitabine in pancreatic cancer.

Background: Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population.

Species differences in troxacitabine pharmacokinetics and pharmacodynamics: implications for clinical development.

Purpose: Troxacitabine is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Significant differences in troxacitabine toxicity between mice, rats, monkeys, and humans were observed during preclinical and clinical evaluations. To better understand the different toxicity and efficacy results observed between the human xenograft mouse tumor models used for preclinical assessment and the clinical study results, the pharmacodynamics and pharmacokinetics of troxacitabine were reassessed in murine and human models.

Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents.

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as potent apoptosis inducers through a cell-based high throughput screening assay. Six compounds from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-116407, and MX-126303, were further profiled and shown to have potent in vitro cytotoxic activity toward proliferating cells only and to interact with tubulin at the colchicine-binding site, thereby inhibiting tubulin polymerization and leading to cell cycle arrest and apoptosis. Furthermore, these compounds were shown to disrupt newly formed capillary tubes in vitro at low nanomolar concentrations.

Complementary antineoplastic activity of the cytosine nucleoside analogues troxacitabine (Troxatyl) and cytarabine in human leukemia cells.

Purpose: Troxacitabine (BCH-4556, l-(-)-OddC, Troxatyl) is a novel beta- l-nucleoside analogue with potent antineoplastic activity both in vitro and in several tumor models in vivo, and is presently in phase II clinical trials. The combination of the cytosine analogues troxacitabine and araC (1-beta- d-arabinofuranosylcytosine, cytarabine) has shown promising activity in patients with acute myelogenous leukemia. To further examine the interactions between these two analogues, we investigated the in vitro and in vivo effects of their combination against a human leukemia cell line, CCRF-CEM.

A novel RGD antagonist that targets both alphavbeta3 and alpha5beta1 induces apoptosis of angiogenic endothelial cells on type I collagen.

Integrin-mediated cell adhesion is necessary for endothelial cell proliferation and apoptosis, which is a major determinant in tumor-induced angiogenesis. In this study, we compared two novel, structurally similar, Arg-Gly-Asp (RGD) peptidomimetic compounds having different integrin selectivities, for their inhibition of endothelial cell proliferation and induction of apoptosis on functionally relevant extracellular matrices (ECM) for angiogenesis. BCH-14661 was specific for integrin alphavbeta3, whereas BCH-15046 nonselectively antagonized integrins alphavbeta3, alphavbeta5, and alpha5beta1.

BCH-1868 [(-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl) tetrahydrofuran]: a cyclic nucleoside phosphonate with antitumor activity.

Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum of antiviral activity. However, only a few of them are reported to have antitumor activity. In this study, we show that a tetrahydrofuran phosphonate analogue of guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl) tetrahydrofuran (BCH-1868), previously reported as having antiviral activity, also displays antitumor activity.

Novel bicyclic lactam inhibitors of thrombin: highly potent and selective inhibitors.

The potency and selectivity of a previous series of low molecular weight thrombin inhibitors were improved through modifications of the P1 and P3 residues. Introduction of diphenyl substituted sulfonamides in the P3 moiety led to highly efficacious compounds. By correctly selecting the combination of P1 and P3 residues, high levels of potency, selectivity and in vivo efficacy were obtained.

Differential roles for nicotinic and muscarinic cholinergic receptors in sustained visuo-spatial attention? A study using a 5-arm maze protocol in mice.

A 5-arm maze was used to measure sustained visuo-spatial attention in C57Bl/6 mice and test the hypothesis of differential functional roles for central nicotinic and muscarinic receptors in mediating task performance. Mice were first trained to acquire the basic visual discrimination task in which, on each trial, one randomly chosen arm among the five open arms was baited and remained lit until an arm-choice was made. Mice were then submitted to attentional testing in which trials using light signals of 2, 1 or 0.

Novel bicyclic lactam inhibitors of thrombin: potency and selectivity optimization through P1 residues.

Peptidomimetic inhibitors of thrombin lacking the important Ser195-carbonyl interaction have been prepared. The binding energy lost after the removal of the activated carbonyl was recaptured through a series of modifications of the P1 residues of the bicyclic lactam inhibitors. Selected substituted compounds displayed useful pharmacological profiles both in vitro and in vivo.

Potent and selective bicyclic lactam inhibitors of thrombin. Part 4: transition state inhibitors.

Bicyclic piperazinone based thrombin inhibitors of general structure 2 were prepared and evaluated in vitro and in vivo. These inhibitors, having in common an electrophilic basic trans-cyclohexylamine P1 residue, displayed high thrombin affinity, high selectivity against trypsin and good in vivo efficacy in the rat arterial thrombosis model.

In vitro and in vivo properties of bicyclic lactam inhibitors: a novel class of low molecular weight peptidomimetic thrombin inhibitors.

We have developed potent and selective thrombin inhibitors with a novel non-peptidic structure. A bicyclic lactam was used as the scaffold on which various P1 and P3 motifs were substituted. Herein, we report the in vitro and in vivo properties of four representatives of this novel class of inhibitors.

A 5-arm maze enables parallel measures of sustained visuo-spatial attention and spatial working memory in mice.

A 5-arm maze has been developed to provide parallel tests of sustained visuo-spatial attention and spatial working memory in mice. C57Bl/6 mice were trained to select, either by immediate response (attention) or by delayed-matching response (working memory), one target arm among the five open arms. For attention testing, mice were first trained to acquire the basic task in which one randomly selected baited arm remained lit until a choice was made.

Incorporation of an Asp-Ser sequence to form an RGDS-like motif in hirutonin: the effect on in vitro platelet function.

We investigated the effect on in vitro platelet function of hirutonin, a modified hirutonin with an RGD-like motif, a pseudo-RGDS peptide and a linear RGDS peptide. Inhibition of expression of surface fibrinogen on ADP-activated platelets with 40 microM of the peptide was as follows: hirutonin 10+/-3%, modified chimeric peptide 26+/-5%, pseudo-RGDS 66+/-11% and linear RGDS 93+/-13%. Both hirutonin and the chimeric peptide significantly inhibited ADP-induced platelet activation as detected by CD62 expression.

A retrospective evaluation of the causes of death of 448 insured French horses in 1995.

Epidemiological studies should allow comparisons to be made of the prevalence of disease in populations from different countries, but the population characteristics and health problems in French horses are not well established. We have conducted a retrospective evaluation of the causes of death and vital characteristics of insured horses in France for the year 1995, with a view to comparison with published data from other countries. Files on 448 deceased horses were provided by nine insurance companies.

The design of potent and selective inhibitors of thrombin utilizing a piperazinedione template: part 2.

Potent and selective thrombin inhibitors have been prepared with a piperazinedione template and L-amino acids. Likewise, incorporation of D-amino acids led to potent inhibitors with a novel mode of binding. Herein, the structure activity relationships and structural aspects of these compounds will be described.

Insertion of the Asp-Ser/Phe sequence in the P' position of hirutonin provides molecules having both antithrombin and disintegrin activity.

We have developed novel synthetic peptides that display both antithrombin and disintegrin activity. These peptides were derived from hirutonins, a class of potent proteolytically resistant thrombin inhibitors, in which a dipeptidyl sequence, Asp-Phe or Asp-Ser, was introduced after the proteolytically resistant ketomethylene arginyl glycine isostere. These modified hirutonins inhibited the amidolytic activity of alpha-thrombin (Ki approximately 35 nM), prevented fibrinogen clotting (dTT approximately 100 nM) and inhibited human platelet aggregation and 5-hydroxytryptamine secretion induced by alpha-thrombin (IC50 approximately 600 nM).

Potent bicyclic lactam inhibitors of thrombin: Part I: P3 modifications.

Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.

Evaluation of proteinase-activated receptor-1 (PAR1) agonists and antagonists using a cultured cell receptor desensitization assay: activation of PAR2 by PAR1-targeted ligands.

We developed a calcium signaling-based assay, using cultured human embryonic kidney cells (HEK), that evaluates simultaneously, the activation/desensitization or blockade of the proteinase-activated receptors, PAR1 and PAR2. Using this assay, we analyzed the actions of a number of previously described putative PAR1-targeted peptide agonists and antagonists. We found that most of the previously described PAR1-targeted agents can also activate/desensitize PAR2, and most of these peptides can also activate a calcium signaling pathway in a target cell that possesses PAR2 along with PAR1.