Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice

Lenalidomide is a synthetic derivative of thalidomide exhibiting multiple immunomodulatory activities beneficial in the treatment of several hematological malignancies. Murine pharmacokinetic characterization necessary for translational and further preclinical investigations has not been published. Studies herein define mouse plasma pharmacokinetics and tissue distribution after intravenous (IV) bolus administration and bioavailability after oral and intraperitoneal delivery. Range finding studies used lenalidomide concentrations up to 15 mg/kg IV, 22.5 mg/kg intraperitoneal injections (IP), and 45 mg/kg oral gavage (PO). Pharmacokinetic studies evaluated doses of 0.5, 1.5, 5, and 10 mg/kg IV and 0.5 and 10 mg/kg doses for IP and oral routes. Liquid chromatography–tandem mass spectrometry was used to quantify lenalidomide in plasma, brain, lung, liver, heart, kidney, spleen, and muscle. Pharmacokinetic parameters were estimated using noncompartmental and compartmental methods. Doses of 15 mg/kg IV, 22.5 mg/kg IP, and 45 mg/kg PO lenalidomide caused no observable toxicity up to 24 h postdose. We observed dose-dependent kinetics over the evaluated dosing range. Administration of 0.5 and 10 mg/kg resulted in systemic bioavailability ranges of 90–105% and 60–75% via IP and oral routes, respectively. Lenalidomide was detectable in the brain only after IV dosing of 5 and 10 mg/kg. Dose-dependent distribution was also observed in some tissues. High oral bioavailability of lenalidomide in mice is consistent with oral bioavailability in humans. Atypical lenalidomide tissue distribution was observed in spleen and brain. The observed dose-dependent pharmacokinetics should be taken into consideration in translational and preclinical mouse studies.
An Effective Fluid-Structure Interaction Formulation for Vascular Dynamics by Generalized Robin Conditions

In this work we focus on the modeling and numerical simulation of the fluid-structure interaction mechanism in vascular dynamics. We first propose a simple membrane model to describe the deformation of the arterial wall, which is derived from the Koiter shell equations and is applicable to an arbitrary geometry. Secondly, we consider a reformulation of the fluid-structure problem, in which the newly derived membrane model, thanks to its simplicity, is embedded into the fluid equations and will appear as a generalized Robin boundary condition. The original problem is then reduced to the solution of subsequent fluid equations defined on a moving domain and may be achieved with a fluid solver only. We also derive a stability estimate for the resulting numerical scheme. Finally, we propose new outflow absorbing boundary conditions, which are easy to implement and allow us to reduce significantly the spurious pressure wave reflections that typically appear in artificially truncated computational domains. We present several numerical results showing the effectiveness of the proposed approaches.
Qualitative Analysis of a Prey-Predator Model with Stage Structure for the Predator

In this paper, we propose a diffusive prey-predator model with stage structure for the predator. We first analyze the stability of the nonnegative steady states for the reduced ODE system and then study the same question for the corresponding reaction-diffusion system with homogeneous Neumann boundary conditions. We find that a Hopf bifurcation occurs in the ODE system, but no Turing pattern happens in the reaction-diffusion system. However, when a natural cross diffusion term is included in the model, we can prove the emergence of stationary patterns (i.e., nonconstant positive stationary solutions) for this system; moreover, these stationary patterns do not exist in the considered parameter regime when there is no cross diffusion.
Analysis of the Multiplane Method for Stochastic Simulations of Reaction Networks with Fluctuations

Chemical reaction networks are commonly modeled by rate equations, which are systems of ordinary differential equations describing the evolution of species concentrations. Such models break down at low concentrations, where stochastic effects become dominant. Instead, one has to solve the master equation that governs the multidimensional probability distribution of particle populations. For large networks such an approach is often computationally prohibitive due to the exponential dependence of the number of states on the number of components. The multiplane method is a dimension reduction technique that exploits the structure of the network to derive approximate dynamics for the marginal distributions of pairs of coreacting species. This method was introduced in [A. Lipshtat and O. Biham, Phys. Rev. Lett. , 93 (2004), 170601] as an uncontrolled approximation for specific examples in the context of interstellar chemical reactions. In this paper we formalize the method and prove that it is asymptotically ex.
Bounds for the Effective Stress of Classical and Strain Gradient Plastic Composites

Given an average strain, rigorous bounds are established for the stress in a deformation of a plastic composite material, which follows a power law. The deformation theory of strain gradient plasticity, which introduces an internal material length scale, is used. It falls into the classical deformation theory of elasto-plasticity when this length scale equals zero. The method employs the idea by Milton and Serkov [J. Mech. Phys. Solids, 48 (2000), pp. 1259–1324] and other techniques for bounding effective energy. We derive two stress bounds which closely relate to the Reuss lower bound and the Hashin–Shtrikman upper bound for the energy. We then study numerically the dependence on the internal length scale of the magnitude of the stress and the region in the stress space determined by these two bounds in which the macro stress must lie. The results confirm the prediction made by Fleck and Willis [J. Mech. Phys. Solids, 52 (2004), pp. 1855–1888] for the macroscopic uniaxial response by differentiating thei.
Propagation of Local Disturbances in Reaction Diffusion Systems Modeling Quadratic Autocatalysis

This article studies the propagation of initial disturbance in a quadratic autocatalytic chemical reaction in one-dimensional slab geometry, where two chemical species A, called the reactant, and B, called the autocatalyst, are involved in the simple scheme $A+B\rightarrow2B$. Experiments demonstrate that chemical systems for which quadratic or cubic catalysis forms a key step can support propagating chemical wavefronts. When the autocatalyst is introduced locally into an expanse of the reactant, which is initially at uniform concentration, the developing reaction is often observed to generate two wavefronts, which propagate outward from the initial reaction zone. We show rigorously that with such an initial setting the spatial region is divided into three regions by the two wavefronts. In the middle expanding region, the reactant is almost consumed so that $A\approx0$, whereas in the other two regions there is basically no reaction so that $B\approx0$. Most of the chemical reaction takes place near the w.
Survival of spray-dried and free-cells of potential probiotic Lactobacillus plantarum 564 in soft goat cheese.

A high viability of probiotics in food product, with a living cells threshold of 107 /cfu/g (colony-forming units/g) is a challenge to achieve in food production. Spray drying is an efficient and economic industrial method for probiotic bacterial preservation and its application in food products. In this study, the survival of free and spray-dried cells of potential probiotic strain Lactobacillus plantarum 564 after production and during 8 weeks of storage of soft acid coagulated goat cheese was investigated, as well as compositional and sensory quality of cheese. Total bacterial count of spray-dried Lb. plantarum 564 cells were maintained at the high level of 8.82 log/cfu/g in cheese after 8 weeks of storage, while free-cell number decreased to 6.9 log/cfu/g. However, the chemical composition, pH values and sensory evaluation between control cheese (C1 sample made with commercial starter culture) and treated cheese samples (C2 and C3, made with the same starter, with the addition of free and spray-dried Lb. plantarum 564 cells, respectively) did not significantly differ. High viability of potential probiotic bacteria and acceptable sensory properties indicate that spray-dried Lb. plantarum 564 strain could be successfully used in the production of soft acid coagulated goat cheeses.
Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-like-peptide-1 receptor stimulation.

The effects of peripheral glucagon like peptide-1 receptor (GLP-1R) stimulation on feeding, gastric emptying, and energetic responses involve vagal transmission and central nervous system processing. Despite a lack of studies aimed at determining which central nervous system regions are critical for the GLP-1R response production, hypothalamic/forebrain processing is regarded as essential for these effects. Here the contribution of the caudal brainstem to the control of food intake, core temperature, heart rate, and gastric emptying responses generated by peripheral delivery of the GLP-1R agonist, exendin-4 (Ex-4), was assessed by comparing responses of chronic supracollicular decerebrate (CD) rats to those of pair-fed intact control rats. Responses driven by hindbrain intracerebroventricular (fourth i.c.v) delivery of Ex-4 were also evaluated. Intraperitoneal Ex-4 (1.2 and 3.0 microg/kg) suppressed glucose intake in both CD rats (5.0+/-1.2 and 4.4+/-1.1 ml ingested) and controls (9.4+/-1.5 and 7.7+/-0.8 ml ingested), compared with intakes after vehicle injections (13.1+/-2.5 and 13.2+/-1.7 ml ingested, respectively). Hindbrain ventricular Ex-4 (0.3 microg) also suppressed food intake in CD rats (4.7+/-0.6 ml ingested) and controls (11.0+/-2.9 ml ingested), compared with vehicle intakes (9.3+/-2.1 and 19.3+/-4.3 ml ingested, respectively). Intraperitoneal Ex-4 (0.12, 1.2, 2.4 microg/kg) reduced gastric emptying rates in a dose-related manner similarly for both CD and control rats. Hypothermia followed ip and fourth i.c. v Ex-4 in awake, behaving controls (0.6 and 1.0 C average suppression) and CD rats (1.5 and 2.5 C average suppression). Intraperitoneal Ex-4 triggered tachycardia in both control and CD rats. Results demonstrate that caudal brainstem processing is sufficient for mediating the suppression of intake, core temperature, and gastric emptying rates as well as tachycardia triggered by peripheral GLP-1R activation and also hindbrain-delivered ligand. Contrary to the literature, hypothalamic/forebrain processing and forebrain-caudal brainstem communication is not required for the observed responses.
Fosaprepitant dimeglumine (MK-0517 or L-785,298), an intravenous neurokinin-1 antagonist for the prevention of chemotherapy induced nausea and vomiting

Background: This paper reviews the existing literature on fosaprepitant, an intravenous neurokinin-1 anatgonist for the prevention of chemotherapy induced nausea and vomiting. Objectives: To describe the development of fosaprepitant and to situate the intravenous form of aprepitant in the current market of available antiemetics. Methods: Literature was screened and selected in order to compare the intravenous form of the already commonly used NK-1 receptor antagonist aprepitant. Results: Aprepitant is the first and still the only marketed neurokinin-1 (NK-1) antagonist. Interestingly, the first studies were performed with fosaprepitant dimeglumine (MK-0517 or L-785,298), the water-soluble prodrug of aprepitant. Fosaprepitant is converted into aprepitant within 30 min after intravenous administration. Based on equivalence studies, 115 mg fosaprepitant seems to be the substitute for 125 mg orally administrated aprepitant. Tolerability of the prodrug is no different from the active drug. The number of efficacy studies with fosaprepitant is very limited and most data are derived from existing aprepitant results. Fosaprepitant has recently been approved by FDA and EMEA as an intravenous substitute for oral aprepitant on day 1 of the standard 3-day CINV prevention regimen, which also includes dexamethasone and a 5-HT3 antagonist.
HIV Prevention for Intimate Couples: A Relationship-Based Model

HIV prevention programs targeted to heterosexuals have most often been delivered in individual or group modalities that principally focus on women as the agents of change. To date, most HIV risk-reduction interventions are not specifically designed to address issues involving intimate couples or to include both partners. Approaches which take into account relationship dynamics and communication patterns are needed to enable women to initiate or sustain condom use with their main steady partners. In this paper, we present a relationship-based HIV intervention, Project Connect, delivered to 217 African American and Latino heterosexual couples recruited from primary healthcare settings. The paper will first discuss the rationale and the conceptual framework underlying the intervention and then elaborate on the intervention components. Finally, lessons learned in the implementation of the project and implications of Project Connect to future practice and policy making for HIV interventions for heterosexual couples will be discussed.
On the Accuracy of the Numerical Detection of Complex Obstacles from Far Field Data Using the Probe Method

We deal with the acoustic inverse scattering problem for detecting an obstacle with mixed boundary conditions from the far field map. We show how the geometrical properties and the material parameter distributed on the surface are involved in the obstacle reconstruction numerically. The main advance of this research is the numerical analysis and implementation of our recent theoretical work [J.J. Liu and M. Sini, How to make the reconstruction of obstacles more (or less) accurate from exterior measurements, RICAM preprint 2008-04, Johann Radon Institute for Computational and Applied Mathematics, Linz, Austria, 2008] regarding the higher order asymptotic expansion of the probe indicator function and the introduction of complex-valued surface impedance. An efficient numerical implementation scheme is proposed based on the properties of minimum norm solutions. Precisely, using the relation between the surface impedance and the obstacle curvature contained in the higher order expansion of the indicators, we reveal how the obstacle curvature and the surface impedance on the coated part influence the blowing-up behavior. Using this theoretical result, we can specify the complex surface impedance in terms of the obstacle curvature to make the reconstruction more (or less) accurate. By establishing properties of the minimum norm solution for approximating the singular sources, efficient realizations for approximating the multipoles by the Herglotz wave function and therefore the implementations of the probe methods are developed with an error estimate. We finally show extensive numerical tests explaining how and to what extent the coupling relation between the curvature and the surface impedance changes the accuracy of the reconstruction of the obstacles.
Piroxicam and doxycycline treatment for an oral squamous cell carcinoma in an inshore bottlenose dolphin (Tursiops aduncus).

BACKGROUND The virus family Papillomaviridae has been documented in a wide range of animal species and can cause benign and malignant proliferative lesions. The presence of concurrent lingual papillomas and squamous cell carcinomas (SCC) in cetaceans has also been documented in both wild and captive populations, suggesting malignant transformation of benign papilloma to SCC may occur in this species. CASE REPORT In 2008, a 38-year-old captive male inshore bottlenose dolphin (Tursiops aduncus) was diagnosed with papillomatous lesions on the intermandibular frenulum rostral to the tongue and an infiltrative SCC of the soft palate following biopsy and histological analysis. A treatment regimen of piroxicam and doxycycline was initiated with misoprostol as a gastroprotectant. The treatment resulted in a marked reduction in tumour size and reversible hepatotoxicosis. Subsequent biopsies revealed the presence of SCC in the oral cavity; however, the disease remains stable at the time of writing. CONCLUSION To the best of our knowledge, this case is the first report of piroxicam and doxycycline used to treat SCC in a bottlenose dolphin. The treatment was successful in reducing the clinical presentation of the disease.
Adrenaline inhibits lipopolysaccharide-induced macrophage inflammatory protein-1α in human monocytes: The role of β-adrenergic receptors

Macrophage inflammatory protein-1α (MIP-1α) has an important role in the development of inflammatory responses during infection by regulating leukocyte trafficking and function. Our study was conducted to investigate the effect of adrenaline on lipopolysaccharide (LPS)-induced MIP-1α production by human peripheral blood monocytes and human monocytic THP-1 cells. Monocytes were incubated in vitro with LPS for 4 h at 37°C in the presence and absence of adrenaline and/or specific α- and β-adrenergic receptor antagonists and agonists. The effects of adrenaline on MIP-1α synthesis were studied at the protein level by using enzyme-linked immunosorbent assays and at the messenger RNA level by using reverse transcriptase-polymerase chain reaction. Adrenaline inhibited LPS-induced MIP-1α production in a dose-dependent manner. The suppressive effect could be completely prevented by propranolol, but not by phentolamine. The specific β-adrenergic agonist isoproterenol produced the same inhibitory effect on LPS-induced MIP-1α production, whereas the α-adrenergic agonist phenylephrine had a minimal effect. In addition, suppression of MIP-1α production was associated with an increase of intracellular cyclic adenosine monophosphate (cAMP) by the cell membrane-permeable cAMP analog dibutyryl-cAMP. Furthermore, we found that adrenaline inhibited LPS-induced MIP-1α messenger RNA expression. These findings suggest that adrenaline can modulate MIP-1α production in inflammatory diseases and sepsis.
E‐pharmacovigilance: development and implementation of a computable knowledge base to identify adverse drug reactions

Computer‐assisted signal generation is an important issue for the prevention of adverse drug reactions (ADRs). However, due to poor standardization of patients' medical data and a lack of computable medical drug knowledge the specificity of computerized decision support systems for early ADR detection is too low and thus those systems are not yet implemented in daily clinical practice. We report on a method to formalize knowledge about ADRs based on the Summary of Product Characteristics (SmPCs) and linking them with structured patient data to generate safety signals automatically and with high sensitivity and specificity.
Error Analysis of a Fractional Time-Stepping Technique for Incompressible Flows with Variable Density

In this paper we analyze the convergence properties of a new fractional time-stepping technique for the solution of the variable density incompressible Navier-Stokes equations. The main feature of this method is that, contrary to other existing algorithms, the pressure is determined by just solving one Poisson equation per time step. First-order error estimates are proved, and stability of a formally second-order variant of the method is established.
Traveling Pulse Solutions for the Discrete FitzHugh-Nagumo System

The existence of fast traveling pulses of the discrete FitzHugh–Nagumo equation is obtained in the weak-recovery regime. This result extends to the spatially discrete setting the well-known theorem that states that the FitzHugh–Nagumo PDE exhibits a branch of fast waves that bifurcates from a singular pulse solution. The key technical result that allows for the extension to the discrete case is the Exchange Lemma that we establish here for functional differential equations of mixed type.
The nitric oxide pathway and possible therapeutic options in pre‐eclampsia

Pre‐eclampsia is a serious multisystem disorder with diverse clinical manifestations. Although not causal, endothelial dysfunction and reduced nitric oxide bioavailability are likely to play an important role in the maternal and fetal pathophysiology of this condition. Lack of treatment modalities that can target the underlying pathophysiological changes and reverse the endothelial dysfunction frequently leads to iatrogenic preterm delivery of the fetus, causing neonatal morbidity and mortality, and the condition itself is associated with short‐ and longer term maternal morbidity and mortality. Drugs that target various components of the nitric oxide–soluble guanylyl cyclase pathway can help to increase NO bioavailability. The purpose of this review is to outline the current status of clinical research involving these therapeutic modalities in the context of pre‐eclampsia, with the focus being on the following: nitric oxide donors, including organic nitrates and S‐nitrosothiols; l‐arginine, the endogenous precursor of NO; inhibitors of cyclic guanosine 3′,5′‐monophosphate breakdown, including sildenafil; and other novel inhibitors of NO donor metabolism. The advantages and limitations of each modality are outlined, and scope for development into established therapeutic options for pre‐eclampsia is explored.
In vitro effectiveness of antifungal lock solutions on catheters infected with Candida species

The antibiotic lock technique involves filling the catheter lumen with an antibiotic solution and allowing it to dwell for sufficient time to sterilize the infected device. However, antifungal therapy for treating catheterrelated fungal infection in this setting is unknown. In this study, the effectiveness of the commercially available antifungal drugs, which are commonly used in candidemia, were assessed in an in vitro antibiotic lock model. Amphotericin B, caspofungin, fluconazole, itraconazole, and voriconazole were used as lock solutions against catheters infected with slime-forming Candida albicans and Candida parapsilosis. Infected catheters were exposed to each of the antifungal lock solution (300-, 500and 1,000-fold MIC) for 1, 3, 5, and 7 days. The presence of the remaining Candida in the catheter was evaluated quantitatively. Among the antifungal agents, amphotericin B and caspofungin lock solutions decreased the yeast colony count significantly from baseline starting on the first day of treatment (P \ 0.001). Significant decrease in the colony count continued, and the catheters were completely sterile at the fifth day. Fluconazole, itraconazole, and voriconazole lock solutions failed to sterilize the catheters, and the numbers of yeast colonies were[10 at the end of the study. In summary, amphotericin B and caspofungin appear to have unique activities against Candida-infected catheters. It seems that one of these drugs may permit the retention of an affected intravascular catheter by sterilizing it in a few days.