Transdermal drug delivery is a passive diffusion process of an active compound through the skin which is affected by drug solubility in the multilamellar lipidic matrix of the stratum corneum (SC). Widely used non-ionic surfactants (NIS) can be added into transdermal formulations to enhance the penetration of drugs by influencing the packing of the stratum corneum lipidic matrix. Objective of our study was to analyse the interaction between selected NIS and a simple SC lipidic matrix model system using a variety of surface-sensitive techniques based on the application of Langmuir monolayers. In this work, the well-known surfactant Polysorbate 80 was compared with a modern surfactant Sucrose monolaurate. Infrared reflection-absorption spectroscopy (IRRAS) and epifluorescence microscopy provide information about the effects of those surfactants on the SC model system. Monolayer isotherms of the SC model mixture indicate a very stiff and well-packed layer, however, packing defects are evidenced in epifluorescence studies. The injection of the two NIS underneath the SC monolayers proved their potential to penetrate into the SC model at the air-water interface having a maximum insertion pressure (MIP) above the assumed lateral pressure of biological membranes. The NIS adsorbed preferentially into packing defects seen in epifluorescence microscopy studies with Sucrose monolaurate being more active than Polysorbate 80 in disordering the SC monolayer.
- Keywords
- Epifluorescence microscopy, IRRAS, Langmuir monolayer, Non-ionic surfactants, Penetration enhancers, Polysorbate 80, Stratum Corneum, Sucrose monolaurate,
- MeSH
- Administration, Cutaneous MeSH
- Models, Biological MeSH
- Skin * MeSH
- Lipids MeSH
- Surface-Active Agents * MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Lipids MeSH
- Surface-Active Agents * MeSH
The presented article demonstrates the probabilistic method based modeling of the 2D chloride ingress into reinforced concrete structures with respect to concrete heterogeneity and epoxy-coated steel reinforcement. Spatial change of concrete diffusion is assessed through the investigation of random variation of the ability of concrete to resist chloride ingress. Time-dependent chloride concentration at the reinforcement level in both homogeneous and heterogeneous models is comparatively considered taking into account of the influence of reinforcement protection as well as the defects and holidays of the coating. Expansion optimal linear estimation method is exploited to generate a random field for the structure at the mesoscale and correlation length is employed to simplify the modeling process. Preliminary analyses of the built model are conducted in both deterministic and probabilistic solutions under the scheme of the finite element method. Thus, possibility of such analyses is exploited.
- Keywords
- 2D diffusion model, chloride penetration, coatings, concrete heterogeneity, random fields, reinforcement protection,
- Publication type
- Journal Article MeSH
Multitime correlation functions provide useful probes for the ensembles of trajectories underlying the stochastic dynamics of complex systems. These can be obtained by measuring their optical response to sequences of ultrashort optical pulse. Using the continuous time random walk model for spectral diffusion, we analyze the signatures of anomalous relaxation in two-dimensional four wave mixing signals. Different models which share the same two point joint probability distribution show markedly different lineshapes and may be distinguished. Aging random walks corresponding to waiting time distributions with diverging first moment show dependence of 2D lineshapes on initial observation time, which persist for long times.
- MeSH
- Algorithms MeSH
- Time Factors MeSH
- Diffusion MeSH
- Chemistry, Physical methods MeSH
- Markov Chains MeSH
- Molecular Conformation MeSH
- Normal Distribution MeSH
- Computer Simulation MeSH
- Probability MeSH
- Spectrum Analysis methods MeSH
- Models, Statistical MeSH
- Stochastic Processes MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Signatures of chemical exchange and spectral diffusion in 2D photon-echo line shapes of molecular aggregates are studied using model calculations for a dimer whose Hamiltonian parameters are stochastically modulated. Cross peaks induced by chemical exchange and by exciton transport have different dynamics and distinguish two models which have the same absorption spectrum (a two-state jump bath modulation model of a dimer and a four-state jump bath model of a single chromophore). Slow Gaussian-Markovian spectral diffusion of a symmetric dimer induces new peaks which are damped as the dipole moment is equilibrated. These effects require an explicit treatment of the bath and may not be described by lower-level theories such as the Redfield equations, which eliminate the bath.
A mathematical model of myocardial perfusion based on the lattice Boltzmann method (LBM) is proposed and its applicability is investigated in both healthy and diseased cases. The myocardium is conceptualized as a porous material in which the transport and mass transfer of a contrast agent in blood flow is studied. The results of myocardial perfusion obtained using LBM in 1D and 2D are confronted with previously reported results in the literature and the results obtained using the mixed-hybrid finite element method. Since LBM is not suitable for simulating flow in heterogeneous porous media, a simplified and computationally efficient 1D-analog approach to 2D diseased case is proposed and its applicability discussed.
- Keywords
- advection–diffusion problem, contrast agent transport, lattice Boltzmann method, magnetic resonance imaging, mixed‐hybrid finite element method, myocardial perfusion,
- MeSH
- Finite Element Analysis * MeSH
- Contrast Media MeSH
- Coronary Circulation physiology MeSH
- Humans MeSH
- Models, Cardiovascular * MeSH
- Computer Simulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Contrast Media MeSH
BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. Implementation of high-dose cytarabine (araC) into induction therapy became standard-of-care for all newly diagnosed younger MCL patients. However, many patients relapse even after araC-based regimen. Molecular mechanisms responsible for araC resistance in MCL are unknown and optimal treatment strategy for relapsed/refractory MCL patients remains elusive. METHODS: Five araC-resistant (R) clones were derived by long-term culture of five MCL cell lines (CTRL) with increasing doses of araC up to 50 microM. Illumina BeadChip and 2-DE proteomic analysis were used to identify gene and protein expression changes associated with araC resistance in MCL. In vitro cytotoxicity assays and experimental therapy of MCL xenografts in immunodeficient mice were used to analyze their relative responsiveness to a set of clinically used anti-MCL drugs. Primary MCL samples were obtained from patients at diagnosis and after failure of araC-based therapies. RESULTS: Marked downregulation of deoxycytidine-kinase (DCK) mRNA and protein expression was identified as the single most important molecular event associated with araC-resistance in all tested MCL cell lines and in 50% primary MCL samples. All R clones were highly (20-1000x) cross-resistant to all tested nucleoside analogs including gemcitabine, fludarabine and cladribine. In vitro sensitivity of R clones to other classes of clinically used anti-MCL agents including genotoxic drugs (cisplatin, doxorubicin, bendamustine) and targeted agents (bortezomib, temsirolimus, rituximab) remained unaffected, or was even increased (ibrutinib). Experimental therapy of immunodeficient mice confirmed the anticipated loss of anti-tumor activity (as determined by overall survival) of the nucleoside analogs gemcitabine and fludarabine in mice transplanted with R clone compared to mice transplanted with CTRL cells, while the anti-tumor activity of cisplatin, temsirolimus, bortezomib, bendamustine, cyclophosphamide and rituximab remained comparable between the two cohorts. CONCLUSIONS: Acquired resistance of MCL cells to araC is associated with downregulation of DCK, enzyme of the nucleotide salvage pathway responsible for the first phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. The data suggest that nucleoside analogs should not be used in the therapy of MCL patients, who relapse after failure of araC-based therapies.
- MeSH
- Electrophoresis, Gel, Two-Dimensional MeSH
- Clone Cells MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Cytarabine pharmacology MeSH
- Deoxycytidine analogs & derivatives pharmacology MeSH
- Deoxycytidine Kinase metabolism MeSH
- Down-Regulation drug effects MeSH
- Gemcitabine MeSH
- Mass Spectrometry MeSH
- Cladribine pharmacology MeSH
- Humans MeSH
- Lymphoma, Mantle-Cell drug therapy enzymology genetics MeSH
- Antibodies, Monoclonal, Murine-Derived pharmacology therapeutic use MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Proteomics MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Rituximab MeSH
- Gene Expression Profiling MeSH
- Vidarabine analogs & derivatives pharmacology MeSH
- Blotting, Western MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cytarabine MeSH
- Deoxycytidine MeSH
- Deoxycytidine Kinase MeSH
- fludarabine MeSH Browser
- Gemcitabine MeSH
- Cladribine MeSH
- Antibodies, Monoclonal, Murine-Derived MeSH
- Antineoplastic Agents MeSH
- Rituximab MeSH
- Vidarabine MeSH
Encapsulation of lithium in the confined spaces within individual nanocapsules is intriguing and highly desirable for developing high-performance Li metal anodes. This work aims for a mechanistic understanding of Li encapsulation and its confined growth kinetics inside 1D enclosed spaces. To achieve this, amorphous carbon nanotubes are employed as a model host using in situ transmission electron microscopy. The carbon shells have dual roles, providing geometric/mechanical constraints and electron/ion transport channels, which profoundly alter the Li growth patterns. Li growth/dissolution takes place via atom addition/removal at the free surfaces through Li+ diffusion along the shells in the electric field direction, resulting in the formation of unusual Li structures, such as poly-crystalline nanowires and free-standing 2D ultrathin (1-2 nm) Li membranes. Such confined front-growth processes are dominated by Li {110} or {200} growing faces, distinct from the root growth of single-crystal Li dendrites outside the nanotubes. Controlled experiments show that high lithiophilicity/permeability, enabled by sufficient nitrogen/oxygen doping or pre-lithiation, is critical for the stable encapsulation of lithium inside carbonaceous nanocapsules. First-principles-based calculations reveal that N/O doping can reduce the diffusion barrier for Li+ penetration, and facilitate Li filling driven by energy minimization associated with the formation of low-energy Li/C interfaces.
- Keywords
- 2D Li crystals, Li encapsulation, amorphous carbon nanotubes, in situ TEM, lithium metal anodes, spatially confined growth,
- Publication type
- Journal Article MeSH
Serum antibodies in suspected angiostrongyliasis patient were detected by ELISA. The antibody titre was 1:51,200 in the serum and 1:6,400 in CSF with preadult A. cantonensis antigen. Other tests like AGD and CIEP failed to show any positive reaction with both preadult and adult worm antigens. Experimental infection with 100 A. cantonensis larvae in albino rats indicated positive CIEP reaction in serum from the day 5 to 375 after infection. No precipitin line was seen on the other hand, in AGD during observation period. Different rat groups infected with larval doses of 100, 500, 2,000, and 5,000 showed positive CIEP reaction, on the 21st day of infection when preadult worms were seen in CNS. There was no CIEP reaction when a low dose of 15 larvae was used. Cerebral fluid of rats infected with heavy dose of 5,000 larvae showed positive CIEP reaction on the 21st day.
- MeSH
- Angiostrongylus immunology MeSH
- Enzyme-Linked Immunosorbent Assay MeSH
- Immunodiffusion MeSH
- Immunoelectrophoresis, Two-Dimensional MeSH
- Immunoelectrophoresis MeSH
- Rats MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Nematode Infections diagnosis immunology MeSH
- Antibodies analysis MeSH
- Serologic Tests MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antibodies MeSH
AIM OF THE STUDY: Chronic cardiotoxicity of doxorubicin occurs at least one year after the chemotherapy is finished. As such, it is a serious late complication in patients with malignant lymphomas. The aim of the study was to identify the incidence of late clinical and subclinical doxorubicin cardiotoxicity and cardiopulmonary performance of patients being in remission for five and more years from the initial therapy. GROUP OF PATIENTS: We worked with 96 patients (47 men and 49 women) aged 43 +/- 15 (median 41, 23-79) years. Average period of monitoring was 6.2 +/- 1.5 (median 6.5-10) years. On the basis of therapy protocol, the patients were administered a maximum doxorubicin cumulative dose (CD DOX) of 377 +/- 147 (median 300, 50-880) mg/m2. Additional treatment after initial conventional therapy was performed in 32 patients (33%) due to high risk, progression or relapse of tumour. EXAMINATION METHODS: Patients were examined by resting echocardiography before and after initial therapy, and during follow-up examination after 5 years. Also, dynamic stress echocardiography and spiroergometry were performed during follow-up examination. Left ventricle ejection fraction (LVEF) decrease below 50 %, progressive decrease of LVEF > 10 % as compared with initial value, and decreased peak oxygen intake pVO2 < 20 ml/kg/min were considered as pathological. We also evaluated systolic function and index of myocardial performance (Tei-index). RESULTS: Clinical cardiotoxicity was observed in 4 % of patients, subclinical in 31% of patients. Diastolic dysfunction was found in 38 % of patients; pathological values of Tei-index were noted in 31% of patients. Value of stress increment of LVEF was 13 +/- 4 % (median 12; 5-25). Decreased pVO2 was observed in 15 % of patients. Cardiovascular disease and age > 60 years represent a higher risk of left ventricular dysfunction. Additional treatment after initial therapy represents a higher risk only if diastolic dysfunction is found (OR = 2.37, p < 0.05). Multi-dimensional regression analysis proved the relationship between pathological EF, CD DOX > or = 300 mg/m2, age > 60 years and cardiovascular disease (for CD DOX p < 0.05; age p < 0.01; concomitant cardiovascular disease p < 0.01, with r = 0.57 and p < 0.02 values for the overall model). CONCLUSIONS: The above-mentioned findings should positively influence the approach of oncologists and haematologists to long-term cardiological monitoring (at least with the help of resting echocardiography) in adult patients treated with antracyclines during initial chemotherapy.
- MeSH
- Bleomycin administration & dosage adverse effects MeSH
- Cyclophosphamide administration & dosage adverse effects MeSH
- Dacarbazine administration & dosage adverse effects MeSH
- Adult MeSH
- Doxorubicin administration & dosage adverse effects MeSH
- Ventricular Dysfunction, Left chemically induced MeSH
- Echocardiography MeSH
- Hodgkin Disease drug therapy MeSH
- Remission Induction MeSH
- Middle Aged MeSH
- Humans MeSH
- Lymphoma, Non-Hodgkin drug therapy MeSH
- Heart Diseases chemically induced diagnosis MeSH
- Prednisone administration & dosage adverse effects MeSH
- Antibiotics, Antineoplastic adverse effects MeSH
- Antineoplastic Combined Chemotherapy Protocols administration & dosage adverse effects MeSH
- Aged MeSH
- Heart drug effects MeSH
- Vinblastine administration & dosage adverse effects MeSH
- Vincristine administration & dosage adverse effects MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- English Abstract MeSH
- Journal Article MeSH
- Names of Substances
- Bleomycin MeSH
- Cyclophosphamide MeSH
- Dacarbazine MeSH
- Doxorubicin MeSH
- Prednisone MeSH
- Antibiotics, Antineoplastic MeSH
- Vinblastine MeSH
- Vincristine MeSH
Center line slope (CLS) analysis in 2D infrared spectroscopy has been extensively used to extract frequency-frequency correlation functions of vibrational transitions. We apply this concept to 2D electronic spectroscopy, where CLS is a measure of electronic gap fluctuations. The two domains, infrared and electronic, possess differences: In the infrared, the frequency fluctuations are classical, often slow and Gaussian. In contrast, electronic spectra are subject to fast spectral diffusion and affected by underdamped vibrational wavepackets in addition to Stokes shift. All these effects result in non-Gaussian peak profiles. Here, we extend CLS-analysis beyond Gaussian line shapes and test the developed methodology on a solvated molecule, zinc phthalocyanine. We find that CLS facilitates the interpretation of 2D electronic spectra by reducing their complexity to one dimension. In this way, CLS provides a highly sensitive measure of model parameters describing electronic-vibrational and electronic-solvent interaction.
- Publication type
- Journal Article MeSH
