Amino acids in oral drug delivery:salts, ion-pairs and transcriptomics

Oral drug delivery is considered the most popular route of delivery because of the ease of administration, availability of a wide range of dosage forms and the large surface area for drug absorption via the intestinal membrane. However, besides the unfavourable biopharmaceutical properties of the therapeutic agents, efflux transporters such as Pglycoprotein (P-gp) and multiple resistance proteins (MRP) decrease the overall drug uptake by extruding the drug from the cells. Although, prodrugs have been investigated to improve drug partitioning by masking the polar groups covalently with pre-moieties promoting increased uptake, they present significant challenges including reduced solubility and increased toxicity. The current work investigates the use of amino acids as ion-pairs for three model drugs: indomethacin (weak acid), trimethoprim (weak base) and ciprofloxacin (zwitter ion) in an attempt to improve both solubility and uptake. Solubility was studied by salt formation while creating new routes for uptake across the membranes via amino acids transporter proteins or dipeptidyl transporters was the rationale to enhance absorption. New salts were prepared for the model drugs and the oppositely charged amino acids by freeze drying and they were characterised using FTIR, 1HNMR, DSC, SEM, pH solubility profile, solubility and dissolution. Permeability profiles were assessed using an in vitro cell based method; Caco-2 cells and the genetic changes occurring across the transporter genes and various pathways involved in the cellular activities were studied using DNA microarrays. Solubility data showed a significant increase in drug solubility upon preparing the new salts with the oppositely charged counter ions (ciprofloxacin glutamate salt exhibiting 2.9x103 fold enhancement when compared to the free drug). Moreover, permeability studies showed a 3 fold increase in trimethoprim and indomethacin permeabilities upon ion-pairing with amino acids and more than 10 fold when the zwitter ionic drug was paired with glutamic acid. Microarray data revealed that trimethoprim was absorbed actively via OCTN1 transporters while MRP7 is the main transporter gene that mediates its efflux. The absorption of trimethoprim from trimethoprim glutamic acid ion-paired formulations was affected by the ratio of glutamic acid in the formulation which was inversely proportional to the degree of expression of OCTN1. Interestingly, ciprofloxacin glutamic acid ion-pairs were found to decrease the up-regulation of ciprofloxacin efflux proteins (P-gp and MRP4) and over-express two solute carrier transporters; (PEPT2 and SLCO1A2) suggesting that a high aqueous binding constant (K11aq) enables the ion-paired formulations to be absorbed as one entity. In conclusion, formation of ion-pairs with amino acids can influence in a positive way solubility, transfer and gene expression effects of drugs.

Controlled synthesis of poly(neopentyl p-styrene sulfonate) via reversible addition-fragmentation chain transfer polymerisation

The controlled synthesis of poly(neopentyl p-styrene sulfonate) (PNSS) using RAFT polymerisation has been studied. Selected experimental conditions led to the production of PNSS with variable molecular weights and low dispersities (D{stroke}≤1.50). The controlled synthesis of poly(neopentyl p-styrene sulfonate) (PNSS) using reversible addition-fragmentation chain transfer polymerisation has been studied under a wide range of experimental conditions. PNSS can be used as an organic-soluble, thermally labile precursor for industrially valuable poly(p-styrene sulfonate), widely employed in technologies such as ionic exchange membranes and organic electronics. The suitability of two different chain transfer agents, three solvents, three different monomer concentrations and two different temperatures for the polymerisation of neopentyl p-styrene sulfonate is discussed in terms of the kinetics of the process and characteristics of the final polymer. Production of PNSS with systematically variable molecular weights and low dispersities (D{stroke} ≤1.50 in all cases) has been achieved using 2-azidoethyl 2-(dodecylthiocarbonothioylthio)-2-methylpropionate in anisole at 75°C, with an initial monomer concentration of 4.0molL-1. Finally, a poly(neopentyl p-styrene sulfonate)-b-polybutadiene-b-poly(neopentyl p-styrene sulfonate) (PNSS-b-PBD-b-PNSS) triblock copolymer has been synthesised via azide-alkyne click chemistry. Moreover, subsequent thermolysis of the PNSS moieties generated poly(p-styrene sulfonate) end blocks. This strategy allows the fabrication of amphiphilic copolymer films from single organic solvents without the need for post-deposition chemical treatment.

Multiscale molecular dynamics/hydrodynamics implementation of two dimensional “Mercedes Benz” water model

A multiscale Molecular Dynamics/Hydrodynamics implementation of the 2D Mercedes Benz (MB or BN2D) [1] water model is developed and investigated. The concept and the governing equations of multiscale coupling together with the results of the two-way coupling implementation are reported. The sensitivity of the multiscale model for obtaining macroscopic and microscopic parameters of the system, such as macroscopic density and velocity fluctuations, radial distribution and velocity autocorrelation functions of MB particles, is evaluated. Critical issues for extending the current model to large systems are discussed.

A comparison of the effects of social constructivist and traditional approaches to teaching on students' attitude and achievement in high school chemistry

Current views of the nature of knowledge and of learning suggest that instructional approaches in science education pay closer attention to how students learn rather than on teaching. This study examined the use of approaches to teaching science based on two contrasting perspectives in learning, social constructivist and traditional, and the effects they have on students' attitudes and achievement. Four categories of attitudes were measured using the Upper Secondary Attitude Questionnaire: Attitude towards school, towards the importance of science, towards science as a career, and towards science as a subject in school. Achievement was measured by average class grades and also with a researcher/teacher constructed 30-item test that involved three sub-scales of items based on knowledge, and applications involving near-transfer and far-transfer of concepts. The sample consisted of 202 students in nine intact classrooms in chemistry at a large high school in Miami, Florida, and involved two teachers. Results were analyzed using a two-way analysis of covariance (ANCOVA) with a pretest in attitude as the covariate for attitudes and prior achievement as the covariate for achievement. A comparison of the adjusted mean scores was made between the two groups and between females and males. ^ With constructivist-based teaching, students showed more favorable attitude towards science as a subject, obtained significantly higher scores in class achievement, total achievement and achievement on the knowledge sub-scale of the knowledge and application test. Students in the traditional group showed more favorable attitude towards school. Females showed significantly more positive attitude towards the importance of science and obtained significantly higher scores in class achievement. No significant interaction effects were obtained for method of instruction by gender. ^ This study lends some support to the view that constructivist-based approaches to teaching science is a viable alternative to traditional modes of teaching. It is suggested that in science education, more consideration be given to those aspects of classroom teaching that foster closer coordination between social influences and individual learning. ^

Memorias en voz baja : Transmisión oral intergeneracional: de Os libros arden mal a As voces baixas

Este trabajo analiza la forma en que se desarrolla un traspaso de la experiencia del pasado traumático en dos textos de Manuel Rivas en los que adquiere gran protagonismo el discurso oral. La Guerra Civil española y sus consecuencias son incorporadas a la narrativa de Os libros arden mal y As voces baixas con especial énfasis en las generaciones que no vivieron esos años. Las convergencias entre oralidad y escritura resultan un terreno fértil para considerar la inclusión de voces largamente postergadas debido a silencios impuestos y a la represión de verdades que tardaron en visibilizarse.

Energy Cooperation in Energy Harvesting Communication Systems

In energy harvesting communications, users transmit messages using energy harvested from nature. In such systems, transmission policies of the users need to be carefully designed according to the energy arrival profiles. When the energy management policies are optimized, the resulting performance of the system depends only on the energy arrival profiles. In this dissertation, we introduce and analyze the notion of energy cooperation in energy harvesting communications where users can share a portion of their harvested energy with the other users via wireless energy transfer. This energy cooperation enables us to control and optimize the energy arrivals at users to the extent possible. In the classical setting of cooperation, users help each other in the transmission of their data by exploiting the broadcast nature of wireless communications and the resulting overheard information. In contrast to the usual notion of cooperation, which is at the signal level, energy cooperation we introduce here is at the battery energy level. In a multi-user setting, energy may be abundant in one user in which case the loss incurred by transferring it to another user may be less than the gain it yields for the other user. It is this cooperation that we explore in this dissertation for several multi-user scenarios, where energy can be transferred from one user to another through a separate wireless energy transfer unit. We first consider the offline optimal energy management problem for several basic multi-user network structures with energy harvesting transmitters and one-way wireless energy transfer. In energy harvesting transmitters, energy arrivals in time impose energy causality constraints on the transmission policies of the users. In the presence of wireless energy transfer, energy causality constraints take a new form: energy can flow in time from the past to the future for each user, and from one user to the other at each time. This requires a careful joint management of energy flow in two separate dimensions, and different management policies are required depending on how users share the common wireless medium and interact over it. In this context, we analyze several basic multi-user energy harvesting network structures with wireless energy transfer. To capture the main trade-offs and insights that arise due to wireless energy transfer, we focus our attention on simple two- and three-user communication systems, such as the relay channel, multiple access channel and the two-way channel. Next, we focus on the delay minimization problem for networks. We consider a general network topology of energy harvesting and energy cooperating nodes. Each node harvests energy from nature and all nodes may share a portion of their harvested energies with neighboring nodes through energy cooperation. We consider the joint data routing and capacity assignment problem for this setting under fixed data and energy routing topologies. We determine the joint routing of energy and data in a general multi-user scenario with data and energy transfer. Next, we consider the cooperative energy harvesting diamond channel, where the source and two relays harvest energy from nature and the physical layer is modeled as a concatenation of a broadcast and a multiple access channel. Since the broadcast channel is degraded, one of the relays has the message of the other relay. Therefore, the multiple access channel is an extended multiple access channel with common data. We determine the optimum power and rate allocation policies of the users in order to maximize the end-to-end throughput of this system. Finally, we consider the two-user cooperative multiple access channel with energy harvesting users. The users cooperate at the physical layer (data cooperation) by establishing common messages through overheard signals and then cooperatively sending them. For this channel model, we investigate the effect of intermittent data arrivals to the users. We find the optimal offline transmit power and rate allocation policy that maximize the departure region. When the users can further cooperate at the battery level (energy cooperation), we find the jointly optimal offline transmit power and rate allocation policy together with the energy transfer policy that maximize the departure region.

Effects of two teaching interventions on nursing students’ acquisition of competence in ECG interpretation

Purpose: Nurse ability to recognise patient arrhythmias could contribute to preventing in-hospital cardiac arrest. Research suggests that nurses and nursing students lack competence in electrocardiogram (ECG) interpretation. The aim of this study was to compare the effects of two training strategies on nursing students’ acquisition of competence in ECG interpretation. Materials and methods: A controlled randomised trial with 98 nursing students. Divided in groups of 12–16, participants were randomly allocated to one of the following 3-h teaching intervention groups: 1) traditional instructor-led (TILG), and 2) flipped classroom (FCG). Participants’ competence in ECG interpretation was measured in terms of knowledge (%), skills (%) and self-efficacy (%) using a specifically designed and previously validated toolkit at pre-test and post-test. Two-way MANOVA explored the interaction effect between ‘teaching group’ and ‘time of assessment’ and its impact on participants’ competence. Within-group differences at pre-test and post-test were explored by carrying out paired t-tests. Between-group differences at pre- and post-test were examined by performing independent t-test analysis. Results: There was a statistically significant interaction effect between ‘teaching group’ and ‘time of assessment’ on participants’ competence in ECG interpretation (F(3,190) = 86.541, p = 0.001; Wilks’ Λ = 0.423). At pre-test, differences in knowledge (TILG = 35.12 ± 12.07; FCG = 35.66 ± 10.66), skills (TILG = 14.05 ± 10.37; FCG = 14.82 ± 14.14), self-efficacy (TILG = 46.22 ± 23.78; FCG = 40.01 ± 21.77) and all other variables were non-significant (p > 0.05). At post-test, knowledge (TILG = 55.12 ± 14.16; FCG = 94.2 ± 7.31), skills (TILG = 36.90 ± 16.45; FCG = 86.43 ± 14.32) and self-efficacy (TILG = 70.78 ± 14.55; FCG = 79.98 ± 10.35) had significantly improved, regardless of the training received (p < 0.05). Nonetheless, participants in the FCG scored significantly higher than participants in the TILG in knowledge, skills and self-efficacy (p < 0.05). Conclusion: Flipping the classroom for teaching ECG interpretation to nursing students may be more effective than using a traditional instructor-led approach in terms of immediate acquisition of competence in terms of knowledge, skills and self-efficacy. Further research on the effects of both teaching strategies on the retention of the competence will be undertaken.

Pelvic-Floor Rehabilitation, Part 1 : Comparison of Two Surface Electrode Placements During Stimulation of the Pelvic-Floor Musculature in Women Who Are Continent Using Bipolar Interferential Currents

Background and Purpose. Electrical stimulation of the pelvic floor is used as an adjunct in the conservative treatment of urinary incontinence. No consensus exists, however, regarding electrode placements for optimal stimulation of the pelvic-floor musculature. The purpose of this study was to compare two different bipolar electrode placements, one suggested by Laycock and Green (L2) the other by Dumoulin (D2), during electrical stimulation with interferential currents of the pelvic-floor musculature in continent women, using a two-group crossover design. Subjects. Ten continent female volunteers, ranging in age from 20 to 39 years (X̅=27.3, SD=5.6), were randomly assigned to one of two study groups. Methods. Each study group received neuromuscular electrical stimulation (NMES) of the pelvic-floor musculature using both electrode placements, the order of application being reversed for each group. Force of contraction was measured as pressure (in centimeters of water [cm H2O]) exerted on a vaginal pressure probe attached to a manometer. Data were analyzed using a two-way, mixed-model analysis of variance. Results. No difference in pressure was observed between the two electrode placements. Differences in current amplitude were observed, with the D2 electrode placement requiring less current amplitude to produce a maximum recorded pressure on the manometer. Subjective assessment by the subjects revealed a preference for the D2 electrode placement (7 of 10 subjects). Conclusion and Discussion. The lower current amplitudes required with the D2 placement to obtain recordings comparable to those obtained with the L2 technique suggest a more comfortable stimulation of the pelvic-floor muscles. The lower current amplitudes required also suggest that greater increases in pressure might be obtained with the D2 placement by increasing the current amplitude while remaining within the comfort threshold. These results will help to define treatment guidelines for a planned clinical study investigating the effects of NMES and exercise in the treatment of urinary stress incontinence in women postpartum.

Synthesis of indium nanoparticles at ambient temperature; simultaneous phase transfer and ripening

The synthesis of size-monodispersed indium nanoparticles via an innovative simultaneous phase transfer and ripening method is reported. The formation of nanoparticles occurs in a one-step process instead of well-known two-step phase transfer approaches. The synthesis involves the reduction of InCl3 with LiBH4 at ambient temperature and although the reduction occurs at room temperature, fine indium nanoparticles, with a mean diameter of 6.4 ± 0.4 nm, were obtained directly in non-polar n-dodecane. The direct synthesis of indium nanoparticles in n-dodecane facilitates their fast formation and enhances their size-monodispersity. In addition, the nanoparticles were highly stable for more than 2 months. The nanoparticles were characterised by dynamic light scattering (DLS), small angle X-ray scattering (SAXS), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS) and Fourier transform infrared (FT-IR) spectroscopy to determine their morphology, structure and phase purity.

Pelvic-Floor Rehabilitation, Part 1 : Comparison of Two Surface Electrode Placements During Stimulation of the Pelvic-Floor Musculature in Women Who Are Continent Using Bipolar Interferential Currents

Background and Purpose. Electrical stimulation of the pelvic floor is used as an adjunct in the conservative treatment of urinary incontinence. No consensus exists, however, regarding electrode placements for optimal stimulation of the pelvic-floor musculature. The purpose of this study was to compare two different bipolar electrode placements, one suggested by Laycock and Green (L2) the other by Dumoulin (D2), during electrical stimulation with interferential currents of the pelvic-floor musculature in continent women, using a two-group crossover design. Subjects. Ten continent female volunteers, ranging in age from 20 to 39 years (X̅=27.3, SD=5.6), were randomly assigned to one of two study groups. Methods. Each study group received neuromuscular electrical stimulation (NMES) of the pelvic-floor musculature using both electrode placements, the order of application being reversed for each group. Force of contraction was measured as pressure (in centimeters of water [cm H2O]) exerted on a vaginal pressure probe attached to a manometer. Data were analyzed using a two-way, mixed-model analysis of variance. Results. No difference in pressure was observed between the two electrode placements. Differences in current amplitude were observed, with the D2 electrode placement requiring less current amplitude to produce a maximum recorded pressure on the manometer. Subjective assessment by the subjects revealed a preference for the D2 electrode placement (7 of 10 subjects). Conclusion and Discussion. The lower current amplitudes required with the D2 placement to obtain recordings comparable to those obtained with the L2 technique suggest a more comfortable stimulation of the pelvic-floor muscles. The lower current amplitudes required also suggest that greater increases in pressure might be obtained with the D2 placement by increasing the current amplitude while remaining within the comfort threshold. These results will help to define treatment guidelines for a planned clinical study investigating the effects of NMES and exercise in the treatment of urinary stress incontinence in women postpartum.

Influence Of Fluorescent Dye On Physical-mechanical Properties Of Luting Cements For Confocal Microscopy Analysis.

To evaluate the influence of a fluorescent dye (rhodamine B) on the physical and mechanical properties of three different luting cements: a conventional adhesive luting cement (RelyX ARC, 3M/ESPE), a self-adhesive luting cement (RelyX U-200, 3M/ESPE), and a self-etching and self-adhesive luting cement (SeT PP, SDI). The cements were mixed with 0.03 wt% rhodamine B, formed into bar-shaped specimens (n = 10), and light cured using an LED curing unit (Radii, SDI) with a radiant exposure of 32 J/cm(2) . The Knoop hardness (KHN), flexural strength (FS), and Young's modulus (YM) analyses were evaluated after storage for 24 h. Outcomes were subjected to two-way ANOVA and Tukey's test (P = 0.05) for multiple comparisons. No significant differences in FS or YM were observed among the tested groups (P ≥ 0.05); the addition of rhodamine B increased the hardness of the luting cements tested. The addition of a fluorescent agent at 0.03 wt% concentration does not negatively affect the physical-mechanical properties of the luting cement polymerization behavior.

Radiotherapy Does Not Impair Dentin Adhesive Properties In Head And Neck Cancer Patients.

This study evaluated the influence of radiotherapy on the dentin bond strength of teeth extracted from patients who had undergone head and neck radiotherapy. A total of 36 samples were divided into two experimental groups: group I (control group, n = 18) and group II (in vivo irradiated group, n = 18). Groups I and II were further separated into three subgroups (six specimens per subgroup), which were further assigned to the three adhesive system protocols employed: Single Bond 2 (SB) (3M ESPE), Easy Bond (EB) (3M ESPE) and Clearfil SE Bond (CSE) (Kuraray). The adhesive systems were applied to the prepared surface according to the manufacturers' instructions and restored using composite resin (Filtek Supreme, 3M ESPE). After 24 h in deionised water (37(o)C), teeth were horizontally and vertically cut to obtain beam specimens with a cross-section area of 0.8 ± 1.0 mm(2). Specimens were tested in tension using a universal testing machine at a cross-speed of 0.5 mm/min. Fracture patterns were observed under SEM. Data was analysed by two-way analysis of variance (p ≤ 0.05). No statistically significant difference was found between the irradiated (R/SB = 44.66 ± 10.12 MPa; R/EB = 41.48 ± 12.71 MPa; and R/CSE = 46.01 ± 6.98 MPa) and control group (C/SB = 39.12 ± 9.51 MPa; C/EB = 42.40 ± 6.66 MPa; and C/CSE = 36.58 ± 7.06 MPa) for any of the adhesive systems. All groups presented a predominance of mixed fracture modes. Head and neck radiotherapy did not affect dentin bond strength for the adhesive materials tested in this study.

Effect Of Sodium Hypochlorite And Peracetic Acid On The Surface Roughness Of Acrylic Resin Polymerized By Heated Water For Short And Long Cycles.

To evaluate the surface roughness of acrylic resin submitted to chemical disinfection via 1% sodium hypochlorite (NaClO) or 1% peracetic acid (C2H4O3). The disc-shaped resin specimens (30 mm diameter ×4 mm height) were polymerized by heated water using two cycles (short cycle: 1 h at 74°C and 30 min at 100°C; conventional long cycle: 9 h at 74°C). The release of substances by these specimens in water solution was also quantified. Specimens were fabricated, divided into four groups (n = 10) depending on the polymerization time and disinfectant. After polishing, the specimens were stored in distilled deionized water. Specimens were immersed in 1% NaClO or 1% C2H4O3 for 30 min, and then were immersed in distilled deionized water for 20 min. The release of C2H4O3 and NaClO was measured via visual colorimetric analysis. Roughness was measured before and after disinfection. Roughness data were subjected to two-way ANOVA and Tukey's test. There was no interaction between polymerization time and disinfectant in influencing the average surface roughness (Ra, P = 0.957). Considering these factors independently, there were significant differences between short and conventional long cycles (P = 0.012), but no significant difference between the disinfectants hypochlorite and C2H4O3 (P = 0.366). Visual colorimetric analysis did not detect release of substances. It was concluded that there was the difference in surface roughness between short and conventional long cycles, and disinfection at acrylic resins polymerized by heated water using a short cycle modified the properties of roughness.

Spectrophotometric Evaluation Of Dental Bleaching Under Orthodontic Bracket In Enamel And Dentin.

Aware of the diffusion capacity of bleaching in the dental tissues, many orthodontists are subjecting their patients to dental bleaching during orthodontic treatment for esthetic purposes or to anticipate the exchange of esthetic restorations after the orthodontic treatment. For this purpose specific products have been developed in pre-loaded whitening trays designed to fit over and around brackets and wires, with clinical efficacy proven. The objective of this study was to evaluate, through spectrophotometric reflectance, the effectiveness of dental bleaching under orthodontic bracket. Thirty-two bovine incisors crown blocks of 8 mm x 8 mm height lengths were used. Staining of tooth blocks with black tea was performed for six days. They were distributed randomly into 4 groups (1-home bleaching with bracket, 2- home bleaching without bracket, 3- office bleaching with bracket, 4 office bleaching without bracket). The color evaluation was performed (CIE L * a * b *) using color reflectance spectrophotometer. Metal brackets were bonded in groups 1 and 3. The groups 1 and 2 samples were subjected to the carbamide peroxide at 15%, 4 hours daily for 21 days. Groups 3 and 4 were subjected to 3 in-office bleaching treatment sessions, hydrogen peroxide 38%. After removal of the brackets, the second color evaluation was performed in tooth block, difference between the area under the bracket and around it, and after 7 days to verified color stability. Data analysis was performed using the paired t-test and two-way variance analysis and Tukey's. The home bleaching technique proved to be more effective compared to the office bleaching. There was a significant difference between the margin and center color values of the specimens that were subjected to bracket bonding. The bracket bond presence affected the effectiveness of both the home and office bleaching treatments. Key words:Tooth bleaching, spectrophotometry, orthodontics.

Dentine Bond Strength And Antimicrobial Activity Evaluation Of Adhesive Systems.

This study evaluated the dentine bond strength (BS) and the antibacterial activity (AA) of six adhesives against strict anaerobic and facultative bacteria. Three adhesives containing antibacterial components (Gluma 2Bond (glutaraldehyde)/G2B, Clearfil SE Protect (MDPB)/CSP and Peak Universal Bond (PUB)/chlorhexidine) and the same adhesive versions without antibacterial agents (Gluma Comfort Bond/GCB, Clearfil SE Bond/CSB and Peak LC Bond/PLB) were tested. The AA of adhesives and control groups was evaluated by direct contact method against four strict anaerobic and four facultative bacteria. After incubation, according to the appropriate periods of time for each microorganism, the time to kill microorganisms was measured. For BS, the adhesives were applied according to manufacturers' recommendations and teeth restored with composite. Teeth (n=10) were sectioned to obtain bonded beams specimens, which were tested after artificial saliva storage for one week and one year. BS data were analyzed using two-way ANOVA and Tukey test. Saliva storage for one year reduces the BS only for GCB. In general G2B and GCB required at least 24h for killing microorganisms. PUB and PLB killed only strict anaerobic microorganisms after 24h. For CSP the average time to eliminate the Streptococcus mutans and strict anaerobic oral pathogens was 30min. CSB showed no AA against facultative bacteria, but had AA against some strict anaerobic microorganisms. Storage time had no effect on the BS for most of the adhesives. The time required to kill bacteria depended on the type of adhesive and never was less than 10min. Most of the adhesives showed stable bond strength after one year and the Clearfil SE Protect may be a good alternative in restorative procedures performed on dentine, considering its adequate bond strength and better antibacterial activity.