Evaluating the effects of minimum unit pricing in Scotland on the prevalence of harmful drinking: a controlled interrupted time series analysis.

OBJECTIVES: In May 2018, the Scottish Government introduced a minimum unit price (MUP) for alcohol of £0.50 (1 UK unit = 8 g ethanol) to reduce alcohol consumption, particularly among people drinking at harmful levels. This study aimed to evaluate MUP's impact on the prevalence of harmful drinking among adults in Scotland. STUDY DESIGN: This was a controlled interrupted monthly time series analysis of repeat cross-sectional data collected via 1-week drinking diaries from adult drinkers in Scotland (N = 38,674) and Northern England (N = 71,687) between January 2009 and February 2020. METHODS: The primary outcome was the proportion of drinkers consuming at harmful levels (>50 [men] or >35 [women] units in diary week). The secondary outcomes included the proportion of drinkers consuming at hazardous (≥14-50 [men] or ≥14-35 [women] units) and moderate (<14 units) levels and measures of beverage preferences and drinking patterns. Analyses also examined the prevalence of harmful drinking in key subgroups. RESULTS: There was no significant change in the proportion of drinkers consuming at harmful levels (ß = +0.6 percentage points; 95% confidence interval [CI] = -1.1, +2.3) or moderate levels (ß = +1.4 percentage points; 95% confidence interval = -1.1, +3.8) after the introduction of MUP. The proportion consuming at hazardous levels fell significantly by 3.5 percentage points (95% CI = -5.4, -1.7). There were no significant changes in other secondary outcomes or in the subgroup analyses after correction for multiple testing. CONCLUSIONS: Introducing MUP in Scotland was not associated with reductions in the proportion of drinkers consuming at harmful levels but did reduce the prevalence of hazardous drinking. This adds to previous evidence that MUP reduced overall alcohol consumption in Scotland and consumption among those drinking above moderate levels.

Nematic liquid crystal reorientation around multi-walled carbon nanotubes mapped via Raman microscopy.

We have studied the formation of topological defects in liquid crystal (LC) matrices induced by multiwalled carbon nanotubes (MWCNTs) and external electric fields. The defects are ascribable to a distortion of the LC molecular director in proximity of the MWCNT surface. The system is analyzed macroscopically using spectroscopic variable angle ellipsometry. Concurrently, confocal micro-Raman spectroscopy is used to study the system state at the microscale. This allows to acquire a three-dimensional, spatially-resolved map of the topological defect, determining scale length variations and orientation topography of the LC molecules around the MWCNT.

An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach.

Hexavalent chromium (Cr6) is a drinking water contaminant that has been detected in most of the water systems throughout the United States. In 2-year drinking water bioassays, the National Toxicology Program (NTP) found clear evidence of carcinogenic activity in male and female rats and mice. Because reduction of Cr6 to trivalent chromium (Cr3) is an important detoxifying step in the gastrointestinal (GI) tract prior to systemic absorption, models have been developed to estimate the extent of reduction in humans and animals. The objective of this work was to use a revised model of ex vivo Cr6 reduction kinetics in gastric juice to analyze the potential reduction kinetics under in vivo conditions for mice, rats and humans. A published physiologically-based pharmacokinetic (PBPK) model was adapted to incorporate the new reduction model. This paper focuses on the toxicokinetics of Cr6 in the stomach compartment, where most of the extracellular Cr6 reduction is believed to occur in humans. Within the range of doses administered by the NTP bioassays, neither the original nor revised models predict saturation of stomach reducing capacity to occur in vivo if applying default parameters. However, both models still indicate that mice exhibit the lowest extent of reduction in the stomach, meaning that a higher percentage of the Cr6 dose may escape stomach reduction in that species. Similarly, both models predict that humans exhibit the highest extent of reduction at low doses.

Toward hyperuniform disordered plasmonic nanostructures for reproducible surface-enhanced Raman spectroscopy.

We report on the self-assembling of clusters of gold-nanoparticles (Au-NPs) directed by the phase separation of poly(styrene)-b-poly(methylmethacrylate) (PS-b-PMMA) block-copolymer (BCP) on indium tin oxide coated glass, which induces the onset of vertical lamellar domains. After thermal evaporation of gold on BCP, Au-NPs of 4 nm are selectively included into PS-nanodomains by thermal annealing, and then clustered with large density of hot spots (> 10(4) µm(2)) in a random two-dimensional pattern. The resulting nanostructure exhibits near-hyperuniform long-range correlations. The consequent large degree of homogeneity of this isotropic plasmonic pattern gives rise to a highly reproducible Surface-Enhanced Raman Scattering (SERS) enhancement factor over the centimeter scale (std. dev. ∼ 10% over 0.25 cm(2)). We also discuss the application of a static electric field for modulating the BCP host morphology. The electric field induces an alignment of Au-NP clusters into ordered linear chains, exhibiting a stronger SERS activity, but reduced SERS spatial reproducibility.

[Relative bioavailability study of two oral formulations of mycophenolate mofetil in healthy volunteers]. / Estudio de biodisponibilidad relativa entre dos formulaciones orales de micofenolato mofetilo en voluntarios sanos.

BACKGROUND: The bioequivalence of different formulations of a same pharmaceutical product must be tested empirically. AIM: To evaluate the relative bioavailability for an oralformulation of mycophenolate mofetil (MMF) (Linfonex™) compared to the reference formulation (Cellcept™) to determine the bioequivalence between both formulations. MATERIAL AND METHODS: A randomized, crossover, double-blind trial in 22 healthy male volunteers, who received a single oral dose of 1000 mg of Linfonex and Cellcept with a washout period of 10 days. Plasma levels of the drug were determined by high performance liquid chr ornatography. Plasma concentrations were plotted and maximum concentration, area under the plasma concentration versus time between 0 and 12 hours after administration and área under plasma concentration curve versus time after administration between 0 and infinity, were calculated for both products. RESULTS: The active compound, mycophenolic acid, was similarly absorbed in both formulations. No statistically significant differences were found in calculated pharmacokinetic parameters between both formulations. CONCLUSIONS: Linfonex™ 500 mg is bioequivalent to Cellcept™ 500 mg.

Estudio de biodisponibilidad relativa entre dos formulaciones orales de micofenolato mofetilo en voluntarios sanos / Relative bioavailability study of two oral formulations of mycophenolate mofetil in healthy volunteers

Background: The bioequivalence of different formulations of a same pharmaceutical product must be tested empirically. Aim: To evaluate the relative bioavailability for an oralformulation of mycophenolate mofetil (MMF) (Linfonex™) compared to the reference formulation (Cellcept™) to determine the bioequivalence between both formulations. Material and Methods: A randomized, crossover, double-blind trial in 22 healthy male volunteers, who received a single oral dose of 1000 mg of Linfonex and Cellcept with a washout period of 10 days. Plasma levels of the drug were determined by high performance liquid chr ornatography. Plasma concentrations were plotted and maximum concentration, area under the plasma concentration versus time between 0 and 12 hours after administration and área under plasma concentration curve versus time after administration between 0 and infinity, were calculated for both products. Results: The active compound, mycophenolic acid, was similarly absorbed in both formulations. No statistically significant differences were found in calculated pharmacokinetic parameters between both formulations. Conclusions: Linfonex™ 500 mg is bioequivalent to Cellcept™ 500 mg.

Diffusive mixing of polymers investigated by Raman microspectroscopy and microrheology.

Diffusive mixing in a model polymer blend of limited miscibility (i.e., the pair polydimethylsiloxane/polyisobutene) is investigated. The diffusion process is followed in the actual droplet-based microstructure of the polymer blend, as opposed to the ideal planar geometry used in previous studies (Brochard et al. Macromolecules 1983, 16, 1638; Composto et al. Nature 1987, 328, 234). In our experiments we combine Raman microspectroscopy and video particle-tracking microrheology. The first technique allows us to monitor local concentration of the two polymers with high spatial resolution both inside and outside a micrometer-size droplet of the dispersed phase. In addition, microrheology enables to follow how the local viscosity inside the droplet changes during the diffusion. The polymer viscosity inside the droplet is determined by video tracking the Brownian motion of a polystyrene bead microinjected into the droplet. The microspectroscopic and microrheological data are combined to estimate the concentration dependence of the monomer friction factor of the two species, which is a key parameter to calculate the interdiffusion coefficient D. Numerical calculations based on such concentration-dependent interdiffusion coefficient D and several alternative models of the polymer diffusion are compared to the experimental concentration profiles. A satisfactory agreement is found for the so-called "slow theory" (Brochard et al.). A phenomenological model improving the agreement of the model with the experimental data is also presented.

Papel de las enzimas citocromo p450 en el metabolismo de fármacos antineoplásicos: situación actual y perspectivas terapéuticas: [revisión] / Role of cytochrome P450 enzymes in the metabolism of antineoplastic drugs: [review]

Cytochrome P450 enzymes are very important to metabolize anti-carcinogenic agents. Therefore, understanding the role of these enzymes and their allele variants in the bioactivation or detoxification of drugs could greatiy benefit antineoplastic pharmacotherapy. The aim of thís manuscrípt is to give information about metabohzing enzymes for antineoplastic agents and to relate the current situation in antitumoral pharmacotherapy with recent knowledge about cytochrome P450 enzymes. This is crucial for the future perspectives towards personalized pharmacotherapy. We summarize the role of cytochrome P450 enzymes in the resistance and bioactivation of several antitumor agents, their induction and repression mechanisms and the effect of genetic polymorphisms on variability of drug metabolization. The understanding of genetic variability will help to develop new research Unes on innovative therapeutic possibilities.

Farmacocinética de medicamentos de uso pediátrico, visión actual / Pediatric drugs pharmacokinetics

Pharmacokinetics corresponds to the branch of pharmacology that studies the absorption, distribution, biotransformation and excretion of drugs in the body, in order to proportionate a reference line for interpretation of drug concentration in biological fluids, fundamental for clinical therapy. While adult pharmacology has increase greatly, advances in pediatric pharmacology have been poor. Therefore, drug prescription in children is essentially empirical on the basis of an inmature organism. An effective, secure and rational pediatric pharmacology requires exhaustive knowledgement of the developmental changes in relation to absorption, distribution, metabolism and excretion affecting pharmacokinetics parameters; therefore, the effective dose. This review describes fundamental differences between adult and pediatric pharmacokinetics. These differences must be considered when therapeutic strategies develop for newborns and children.

La farmacocinética, rama de la farmacología que estudia el paso de las drogas a través del organismo en función del tiempo y la dosis tiene por finalidad el proporcionar un marco de referencia para interpretar la concentración de los fármacos en los líquidos biológicos por el bien del paciente, lo que es fundamental para una correcta terapéutica clínica. Mientras los avances en farmacología clínica del adulto en las últimas décadas tuvieron un gran adelanto, no ha ocurrido lo mismo en farmacología pediátrica donde la mayoría de las veces la prescripción de medicamentos se realiza sobre una base empírica en un organismo inmaduro. Una terapéutica farmacológica efectiva, segura y racional en neonatos, lactantes y niños requiere el exhaustivo conocimiento de las diferencias en la absorción, distribución, metabolismo y excreción, las que aparecen durante el crecimiento y desarrollo, debido a que virtualmente, todos los parámetros farmacocinéticos se modifican con la edad. Esta revisión describe las diferencias fundamentales en la farmacocinética de los medicamentos en el niño cuando se compara con el adulto. Estas diferencias y los cambios en estos procesos deben ser cuidadosamente considerados cuando se desarrollan estrategias terapéuticas en recién nacidos y niños pequeños.

[Role of cytochrome P450 enzymes in the metabolism of antineoplastic drugs]. / Papel de las enzimas citocromo p450 en el metabolismo de fármacos antineoplásicos: situación actual y perspectivas terapéuticas.

Cytochrome P450 enzymes are very important to metabolize anti-carcinogenic agents. Therefore, understanding the role of these enzymes and their allele variants in the bioactivation or detoxification of drugs could greatly benefit antineoplastic pharmacotherapy. The aim of this manuscript is to give information about metabolizing enzymes for antineoplastic agents and to relate the current situation in antitumoral pharmacotherapy with recent knowledge about cytochrome P450 enzymes. This is crucial for the future perspectives towards personalized pharmacotherapy. We summarize the role of cytochrome P450 enzymes in the resistance and bioactivation of several antitumor agents, their induction and repression mechanisms and the effect of genetic polymorphisms on variability of drug metabolization. The understanding of genetic variability will help to develop new research lines on innovative therapeutic possibilities.

Enhancing Raman tweezers by phase-sensitive detection.

Raman spectroscopy has become a powerful tool for microscopic analysis of organic and biological materials. When combined with optical tweezers (Raman tweezers), it allows investigating single, selected micrometric particles in their natural environment, therefore, reducing unwanted interferences from the cover plate. A general problem affecting both Raman spectrometers and Raman tweezers systems is the background caused by the environment surrounding the sample under investigation. In this paper, we report on a novel method that allows acquiring Raman spectra of a single trapped particle (polystyrene microspheres) free from any background contribution. The method is based on the use of two collinear and copropagating laser beams: the first is devoted to trapping (trap laser), while the second one is used to excite the Raman transitions (pump laser). The trap laser moves the trapped particle periodically, by means of a galvomirror, back and forth across the pump laser. The back-scattered photons are analyzed by a spectrometer and detected by a photomultiplier; finally, the resulting signal is sent to a lock-in amplifier for phase-sensitive detection. The purpose of the present work is to give a detailed description of our method and to supply a systematic study concerning the formation of the Raman signal. We trap polystyrene beads and study the dependence of the Raman signal on several parameters, such as height from the coverslip surface, the bead size, the modulation amplitude, and the pump laser intensity. Our results establish a direct and practical approach for background suppression in the spectroscopic analysis of optical trapped microsized samples.

Work and heat probability distribution of an optically driven Brownian particle: theory and experiments.

We analyze the equations governing the evolution of distributions of the work and the heat exchanged with the environment by a manipulated stochastic system, by means of a compact and general derivation. We obtain explicit solutions for these equations for the case of a dragged Brownian particle in a harmonic potential. We successfully compare the resulting predictions with the outcomes of experiments, consisting of dragging a micron-sized colloidal particle through water with a laser trap.

[Analysis of certain oral health parameters in children with disabilities].

The first permanent molars which show the presence of congenital malocclusions, orthodontic treatment need and habits were studied in children with disabilities and healthy children. The examination covered 80 disabled children and 80 healthy ones (control group) of the age from 3 to 17 (mean age 10) years. Caries of the first permanent molars, bad habits and malocclusions were more common in children with disabilities than in healthy children. It was established that higher orthodontic treatment need was in children with disabilities who were less covered with orthodontic care.

[Angle class I malocclusion in primary dentition and findings in permanent dentition--a follow-up study].

The aim of the study was to examine stability and changes in Angle Class I malocclusion from deciduous to permanent dentition in 168 subjects. All the subjects had Class I malocclusion in deciduous dentition, and were examined by the same orthodontist on two occasions during deciduous and permanent dentition. None of the subjects had received orthodontic therapy in the meantime. The results showed considerable changes from primary to permanent dentition. Crowding in primary dentition was retained in permanent dentition in 45.2% cases. In 16.2% cases it changed into normocclusion and 38.6% subjects developed other types of malocclusion. Open bite was retained in permanent dentition in 17.8% cases and in 17.8% subjects transformed into normocclusion. 64.4% subjects developed other types of malocclusion. Cross bite was retained in permanent dentition in 21.4% cases and in 28.6% subjects changed to normocclusion. Other types of malocclusion in permanent dentition developed in 50% subjects. In 30.8% of cases finding of premature loss of deciduous teeth was accompanied by extraction of some permanent teeth. Normocclusion was retained in 19.2% cases while 50% of children developed some type of malocclusion. Crowding, which was retained in permanent dentition in 45.2% cases, showed the highest degree of stability. Children with this type of anomaly in primary dentition displayed the highest frequency of total malocclusions (83.3% subjects). Out of all anomalies in primary dentition, cross bite most frequently switched to normal occlusion in permanent dentition (in 28.6% cases).

Doppler-free spectroscopy of xenon in the mid-infrared using difference-frequency radiation.

We report on the first Doppler-free spectroscopy investigation of an atomic species, xenon, performed in the mid-infrared using difference-frequency radiation. The absorption saturated spectrum of the xenon 6p[3/2]2?5d[5/2]3 transition (2p6?3d'1 in Paschen notation) at 3.1076 microm was investigated using about 60 microwatts of cw narrowband radiation (Deltanu=50 kHz) generated by difference-frequency mixing in a periodically-poled Lithium Niobate crystal. A single frequency Ti:Sapphire laser (power 800 mW) and a monolithic diode-pumped Nd:YAG laser (300 mW) were used as pump and signal waves respectively. We used natural enriched xenon, which contains nine stable isotopes, two of which, 129Xe and 131Xe, exhibit a hyperfine structure owing to their nuclear spin. The small isotope displacements expected for this atom and the complex hyperfine structure of the odd isotopes make it difficult to fully resolve the recorded saturated-absorption spectra. In spite of this, we have been able to analyze the isolated 129Xe F''=5/2?F'=7/2 hyperfine component by means of first-derivative FM spectroscopy.

Pharmacological suppression of rat distal colon chloride secretion requires two blockers.

Rat distal colon epithelium is frequently employed to assess the effect of natural and synthetic chemicals on chloride secretion. Inhibition of chloride secretion is often reported as the loop diuretic-sensitive portion of short-circuit current (Isc). The present work challenges the hypothesis that a loop diuretic alone is able to fully abolish chloride secretion. Isolated mucosa preparations were mounted in an Ussing chamber. The effects on short-circuit current of replacement of normal Ringer by a low (2.5 mmol/L) Cl solution and of blockers of basolateral Na, K, 2 Cl symport (bumetanide), apical Cl channels (diphenylamine-2-carboxylate, DPC), and anion exchange (4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid, SITS) alone and combined were assessed. Low Cl reversibly decreased Isc by 76%. In normal Ringer, bumetanide decreased Isc by 65%. SITS also had a significant effect at the serosal side, but not at the apical side, where DPC caused a 40% decrease. Chloride replacement, bumetanide and DPC, but not SITS, increased epithelial resistivity. Combined blockade of Na, K, 2 Cl symport and apical Cl channels, of Na, K, 2 Cl symport and anion antiport, or of anion antiport and apical Cl channels was needed to achieve reduction of short circuit current to the same extent seen with chloride replacement. Present results indicate that Isc of the unstimulated epithelium is mostly due to chloride secretion, and at least two blockers are required to abolish it. This fact should be taken into account in studies of chloride secretion-stimulating agents.

Difference-frequency-generator-based spectrometer at 3 mum for high-sensitivity C2H2 and H2O detection.

We detect acetylene and water-vapor lines by using a difference-frequency generator in the spectral region around 3 mm. Both C2H2 and H2O lines belong to fundamental vibrational bands and exhibit a line strength of the order of 10-20 cm/mol. Acetylene molecules were detected either by pure absorption or by first-derivative wavelength-modulation spectroscopy. The minimum detection sensitivity achieved for C2H2 in nitrogen was 4 ppb (parts in 109). Moreover, we discuss the effects of C2H2 pressure reduction in the presence of nitrogen in order to estimate systematic errors in the concentration measurements. Finally, we tested the accuracy of our spectrometer by detecting water vapor present as an impurity in a nitrogen cylinder at a nominal concentration of approximately 5 ppm.

Pharmacological suppression of rat distal colon chloride secretion requires two blockers.

Rat distal colon epithelium is frequently employed to assess the effect of natural and synthetic chemicals on chloride secretion. Inhibition of chloride secretion is often reported as the loop diuretic-sensitive portion of short-circuit current (Isc). The present work challenges the hypothesis that a loop diuretic alone is able to fully abolish chloride secretion. Isolated mucosa preparations were mounted in an Ussing chamber. The effects on short-circuit current of replacement of normal Ringer by a low (2.5 mmol/L) Cl solution and of blockers of basolateral Na, K, 2 Cl symport (bumetanide), apical Cl channels (diphenylamine-2-carboxylate, DPC), and anion exchange (4-acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid, SITS) alone and combined were assessed. Low Cl reversibly decreased Isc by 76

. In normal Ringer, bumetanide decreased Isc by 65

. SITS also had a significant effect at the serosal side, but not at the apical side, where DPC caused a 40

decrease. Chloride replacement, bumetanide and DPC, but not SITS, increased epithelial resistivity. Combined blockade of Na, K, 2 Cl symport and apical Cl channels, of Na, K, 2 Cl symport and anion antiport, or of anion antiport and apical Cl channels was needed to achieve reduction of short circuit current to the same extent seen with chloride replacement. Present results indicate that Isc of the unstimulated epithelium is mostly due to chloride secretion, and at least two blockers are required to abolish it. This fact should be taken into account in studies of chloride secretion-stimulating agents.

Detection and spectroscopy of the v1 + v3 band of N2O by difference-frequency spectrometer at 3 microm.

We report the realisation of a laser spectrometer in the mid-infrared spectral region based on difference-frequency generation in a periodically poled LiNbO3 crystal. Tunable coherent radiation around 3 microm was produced by mixing a diode-pumped monolithic cw Nd-YAG laser and an injection-locked diode laser at 0.785 microm. High sensitivity N2O detection was demonstrated by observing pure absorption spectra of lines in the v1 + v3 combination band. We estimate a minimum detectable pressure of pure N2O of 1 x 10(-2) Pa with 0.9 m absorption path-length, corresponding to an absorbance of 3 x 10(-4). Nitrous oxide was also detected in presence of O2, N2 and air. Collisional broadening coefficients for the P(33) line at 3447.678 per cm are reported for N2O-N2 and N2O-O2 mixtures.