Cryptotanshinone-Induced Permeabilization of Model Phospholipid Membranes: A Biophysical Study.

The Danshen terpenoid cryptotanshinone (CPT) is gaining enormous interest in light of its various outstanding biological activities. Among those, CPT has been shown to interact with cell membranes and, for instance, to have antibacterial activity. Several works have shown that CPT alone, or in combination with other drugs, can effectively act as an antibiotic against various infectious bacteria. Some authors have related the mechanism underlying this action to CPT-membrane interaction. This work shows that CPT readily partitions into phosphatidylcholine membranes, but there is a limiting capacity of accommodation of ca. 1 mol CPT to 3 mol phospholipid. The addition of CPT to unilamellar liposomes composed of 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) causes membrane permeabilization, as shown by fluorescent probe leakage. This process has been kinetically studied, as well as its modulation by incorporation of phosphatidylethanolamine or phosphatidylglycerol, as a model for pathogenic cell membranes. The thermotropic behavior of 1,2-dimyristoylphosphatidylcholine (DMPC) model membranes is weakly affected by CPT, but the terpenoid causes significant dehydration of the polar region of the bilayer and weak disordering of the acyl chain palisade, as observed in Fourier-transform infrared spectroscopy (FTIR) results. Small-angle X-ray scattering (SAXS) shows that CPT increases DMPC bilayer thickness, which could be due to localization near the phospholipid/water interface. Molecular dynamics (MD) simulations show that the lateral diffusion coefficient of the phospholipid increases with the presence of CPT. CPT extends from the polar head region to the center of the bilayer, being centered between the carbonyl groups and the unsaturated region of the POPC, where there is greater overlap. Interestingly, the free energy profiles of a water molecule crossing the lipid membrane show that the POPC membrane becomes more permeable in the presence of CPT. In summary, our results show that CPT perturbs the physicochemical properties of the phospholipid membrane and compromises its barrier function, which could be of relevance to explain part of its antimicrobial or anticancer activities.

On the Mechanism of Membrane Permeabilization by Tamoxifen and 4-Hydroxytamoxifen.

Tamoxifen (TMX), commonly used in complementary therapy for breast cancer, also displays known effects on the structure and function of biological membranes. This work presents an experimental and simulation study on the permeabilization of model phospholipid membranes by TMX and its derivative 4-hydroxytamoxifen (HTMX). TMX induces rapid and extensive vesicle contents leakage in phosphatidylcholine (PC) liposomes, with the effect of HTMX being much weaker. Fitting of the leakage curves for TMX, yields two rate constants, corresponding to a fast and a slow process, whereas in the case of HTMX, only the slow process takes place. Interestingly, incorporation of phosphatidylglycerol (PG) or phosphatidylethanolamine (PE) protects PC membranes from TMXinduced permeabilization. Fourier-transform infrared spectroscopy (FTIR) shows that, in the presence of TMX there is a shift in the νCH2 band frequency, corresponding to an increase in gauche conformers, and a shift in the νC=O band frequency, indicating a dehydration of the polar region. A preferential association of TMX with PC, in mixed PC/PE systems, is observed by differential scanning calorimetry. Molecular dynamics (MD) simulations support the experimental results, and provide feasible explanations to the protecting effect of PG and PE. These findings add new information to explain the various mechanisms of the anticancer actions of TMX, not related to the estrogen receptor, and potential side effects of this drug.

Effects of a Semisynthetic Catechin on Phosphatidylglycerol Membranes: A Mixed Experimental and Simulation Study.

Catechins have been shown to display a great variety of biological activities, prominent among them are their chemo preventive and chemotherapeutic properties against several types of cancer. The amphiphilic nature of catechins points to the membrane as a potential target for their actions. 3,4,5-Trimethoxybenzoate of catechin (TMBC) is a modified structural analog of catechin that shows significant antiproliferative activity against melanoma and breast cancer cells. Phosphatidylglycerol is an anionic membrane phospholipid with important physical and biochemical characteristics that make it biologically relevant. In addition, phosphatidylglycerol is a preeminent component of bacterial membranes. Using biomimetic membranes, we examined the effects of TMBC on the structural and dynamic properties of phosphatidylglycerol bilayers by means of biophysical techniques such as differential scanning calorimetry, X-ray diffraction and infrared spectroscopy, together with an analysis through molecular dynamics simulation. We found that TMBC perturbs the thermotropic gel to liquid-crystalline phase transition and promotes immiscibility in both phospholipid phases. The modified catechin decreases the thickness of the bilayer and is able to form hydrogen bonds with the carbonyl groups of the phospholipid. Experimental data support the simulated data that locate TMBC as mostly forming clusters in the middle region of each monolayer approaching the carbonyl moiety of the phospholipid. The presence of TMBC modifies the structural and dynamic properties of the phosphatidylglycerol bilayer. The decrease in membrane thickness and the change of the hydrogen bonding pattern in the interfacial region of the bilayer elicited by the catechin might contribute to the alteration of the events taking place in the membrane and might help to understand the mechanism of action of the diverse effects displayed by catechins.

Anticancer drugs tamoxifen and 4hydroxytamoxifen as effectors of phosphatidylethanolamine lipid polymorphism.

The interaction of tamoxifen (TMX) and its metabolite 4-hydroxytamoxifen (HTMX) with a biomimetic membrane model system composed of 1,2-dielaidoylphosphatidylethanolamine (DEPE) has been studied using a biophysical approach. Incorporation of TMX into DEPE bilayers gives rise to a progressive broadening of the Lß/Lα phase transition and a downward temperature shift. The Lß/Lα phase transition presents multiple endotherms, indicating a lateral segregation of TMX/DEPE domains within the plane of the bilayer. TMX and HTMX also widen and shift the Lα to hexagonal-HII transition toward lower values, the phase diagrams showing that both compounds facilitate formation of the HII phase. TMX increases motional disorder of DEPE acyl chains in the Lß, Lα and HII phases, whereas the effect of HTMX is clearly different. In addition, neither TMX nor HTMX significantly perturb the hydration state of the polar headgroup region of DEPE. Molecular dynamics (MD) simulations indicate that these drugs do not affect membrane thickness, area per lipid, or the conformation of DEPE molecules. As a general rule, the interaction of HTMX with DEPE is qualitatively similar to TMX but less intense. However, a significant difference shown by MD is that HTMX is mainly placed around the center of each monolayer while TMX is located mainly at the center of the membrane, also having a greater tendency to cluster formation. These results are discussed to understand the modulation of phosphatidylethanolamine lipid polymorphism carried out by these drugs, which could be of relevance to explain their effects on enzyme activity or membrane permeabilization.

3,4,5-Trimethoxybenzoate of Catechin, an Anticarcinogenic Semisynthetic Catechin, Modulates the Physical Properties of Anionic Phospholipid Membranes.

3,4,5-Trimethoxybenzoate of catechin (TMBC) is a semisynthetic catechin which shows strong antiproliferative activity against malignant melanoma cells. The amphiphilic nature of the molecule suggests that the membrane could be a potential site of action, hence the study of its interaction with lipid bilayers is mandatory in order to gain information on the effect of the catechin on the membrane properties and dynamics. Anionic phospholipids, though being minor components of the membrane, possess singular physical and biochemical properties that make them physiologically essential. Utilizing phosphatidylserine biomimetic membranes, we study the interaction between the catechin and anionic bilayers, bringing together a variety of experimental techniques and molecular dynamics simulation. The experimental data suggest that the molecule is embedded into the phosphatidylserine bilayers, where it perturbs the thermotropic gel to liquid crystalline phase transition. In the gel phase, the catechin promotes the formation of interdigitation, and in the liquid crystalline phase, it decreases the bilayer thickness and increases the hydrogen bonding pattern of the interfacial region of the bilayer. The simulation data agree with the experimental ones and indicate that the molecule is located in the interior of the anionic bilayer as monomer and small clusters reaching the carbonyl region of the phospholipid, where it also disturbs the intermolecular hydrogen bonding between neighboring lipids. Our observations suggest that the catechin incorporates well into phosphatidylserine bilayers, where it produces structural changes that could affect the functioning of the membrane.

Interaction of Docetaxel with Phosphatidylcholine Membranes: A Combined Experimental and Computational Study.

The antineoplastic drug Docetaxel is a second generation taxane which is used against a great variety of cancers. The drug is highly lipophilic and produces a great array of severe toxic effects that limit its therapeutic effectiveness. The study of the interaction between Docetaxel and membranes is very scarce, however, it is required in order to get clues in relation with its function, mechanism of toxicity and possibilities of new formulations. Using phosphatidylcholine biomimetic membranes, we examine the interaction of Docetaxel with the phospholipid bilayer combining an experimental study, employing a series of biophysical techniques like Differential Scanning Calorimetry, X-Ray Diffraction and Infrared Spectroscopy, and a Molecular Dynamics simulation. Our experimental results indicated that Docetaxel incorporated into DPPC bilayer perturbing the gel to liquid crystalline phase transition and giving rise to immiscibility when the amount of the drug is increased. The drug promotes the gel ripple phase, increasing the bilayer thickness in the fluid phase, and is also able to alter the hydrogen-bonding interactions in the interfacial region of the bilayer producing a dehydration effect. The results from computational simulation agree with the experimental ones and located the Docetaxel molecule forming small clusters in the region of the carbon 8 of the acyl chain palisade overlapping with the carbonyl region of the phospholipid. Our results support the idea that the anticancer drug is embedded into the phospholipid bilayer to a limited amount and produces structural perturbations which might affect the function of the membrane.

Dissimilar action of tamoxifen and 4-hydroxytamoxifen on phosphatidylcholine model membranes.

The anticancer drug tamoxifen and its primary metabolite 4-hydroxytamoxifen tend to accumulate in membranes due to its strong hydrophobic character. Thus, in this work we have carried out a systematic study to investigate their effects on model phosphatidylcholine membranes. Tamoxifen and 4-hydroxytamoxifen affect the phase behaviour of phosphatidylcholine model membranes, giving rise to formation of drug/dipalmitoylphosphatidylcholine domains, which is more evident in the case of 4-hydroxytamoxifen. These drugs have differential effects on the polar and apolar regions of the phospholipid supporting a different location of both compounds within the bilayer. Both compounds induce contents leakage in fluid phosphatidylcholine unilamellar liposomes, the effect of 4-hydroxytamoxifen being negligible as compared to that of tamoxifen. Molecular dynamics confirmed the tendency of both drugs to form clusters, tamoxifen locating all along the bilayer, whereas 4-hydroxytamoxifen mostly locates near the lipid/water interface, which can explain the different effects of both drugs in fluid phosphatidylcholine membranes.

3D simulation of aneurysm clipping: Data analysis.

Aneurysm clipping requires the proficiency of several skills, yet the traditional way of practicing them has been recently challenged. The use of simulators could be an alternative educational tool. The aim of this data analysis is to provide further evaluation of a reusable low-cost 3D printed training model we developed for aneurysm clipping [1]. The simulator was designed to replicate the bone structure, arteries and targeted aneurysms. Thirty-two neurosurgery residents performed a craniotomy and aneurysm clipping using the model and then filled out a survey. The survey was designed in two parts: a 5-point Likert scale questionnaire and three questions requiring written responses [1]. Two dimensions of the model were evaluated by the questionnaire: the face validity, assessed by 5 questions about the realism of the model, and the content validity, assessed by 6 questions regarding the usefulness of the model during the different steps of the training procedure. The three questions requiring written responses referred to the strengths and weaknesses of the simulator and a global yes/no question as to whether or not they would repeat the experience. Demographic data, experience level and survey responses of the residents were grouped in a dataset [2]. A descriptive analysis was performed for each dimension. Then, the groups were compared according to their level of expertise (Junior and Senior groups) with an independent sample t-test. A Confirmatory Factor Analysis (CFA) was estimated, using a Weighted Least Squares Mean Variance adjusted (WLSMV) which works best for the ordinal data [3]. Fitness was calculated using chi-square (χ2) test, Comparative Fit Index (CFI), Tucker-Lewis Index (TLI), and the Root Mean Square Error of Approximation (RMSEA). A non-significant χ2, CFI and TLI greater than 0.90 and RMSEA < 0.08 were considered an acceptable fit [4]. All data analysis was performed using IBM SPSS 23.0 statistical software. Data are reported as mean + standard deviation (SD). A probability p < 0.05 was considered significant. Exploratory Factor Analysis was done to explore the factorial structure of the 11-items scale in the sample, first we performed a principal components analysis. The Kaiser-Meyer-Olkin measure verified the sampling adequacy for the analysis (KMO = 0.784; Bartlett's Test of Sphericity χ2 (55) = 243.44, p < .001), indicating correlation is adequate for factor analysis. Considering Eigen values greater than 1, a two-factor solution explained 73.1% of the variance but left one item in factor 2 (Q 11). The results of this factor analysis are presented in Table 1. Confirmatory Factor Analysis, considering only the 10 items in the first factor (removing question 11 of our model), was performed. This model reached the following fit: χ2 (35) = 38.821, p > .05; CFI = 0.997; TLI = 0.996; RMSEA 0.058, without any error terms to exhibit covariance. Regarding the reliability of the questionnaire, the internal consistency was explored in the 10 items selected in the confirmatory factor analysis with an alpha coefficient (α = 0.941).

Effect of pH and temperature on the aggregation behaviour of dirhamnolipid biosurfactant. An experimental and molecular dynamics study.

HYPOTHESIS: Pseudomonas aeruginosa dirhamnolipid (diRL) has been shown to form aggregates of different size and structure, under various conditions. Due to the presence of a carboxyl group in the molecule, it is expected that pH would strongly affect this aggregation behaviour. In addition, preliminary observations of temperature-induced changes in the states of aggregation of diRL supported the need of further investigation. EXPERIMENTS: A systematic experimental study, using differential scanning calorimetry (DSC), small-angle Xray diffraction (SAXD), and Fourier-transform infrared spectroscopy (FTIR), has been carried out to characterize pH and temperature driven changes in the aggregation behavior of diRL biosurfactant. Molecular dynamics (MD) simulations, supported by the experimental results, allowed depicting molecular details on formation of diRL membranes and other aggregated structures under various physicochemical conditions. FINDINGS: DiRL could adopt fairly organized multilayered structures (membranes) at low pH and temperature, which became highly disordered upon increasing either of these parameters. The effect of pH on the gauche/all-trans conformer ratio of the diRL acyl chains was not of significance, whereas temperature-induced effects were observed. For the first time it is described that diRL underwent an endothermic thermotropic transition with Tc = 34 °C as observed by DSC, at pH 4.5 (protonated diRL), but not at pH 7.4 (unprotonated diRL). FTIR confirmed these findings, showing a significant additional disordering of the all-trans acyl chains upon increasing temperature around that same value in the protonated form, an effect not observed for the dissociated form of the biosurfactant. In addition, at pH 7.4, changing temperature did not modify the hydration state of the polar moiety of diRL, whereas at pH 4.5 a significant decrease in the hydration state around 34 °C took place. SAXD data showed that protonated diRL formed multilayered structures at 20 °C, which converted into poorly correlated layers at 50 °C. MD simulations supported these findings, showing that the membrane-like structures formed by protonated diRL at 20 °C became unstable at higher temperatures, tending to form other structures, which could be micelles or other type of layered structures, whereas the negatively charged form of diRL organized in micelle-type aggregates in the whole range of temperature under study.

Interaction of a dirhamnolipid biosurfactant with sarcoplasmic reticulum calcium ATPase (SERCA1a).

The interaction of a dirhamnolipid biosurfactant secreted by Pseudomonas aeruginosa with calcium ATPase from sarcoplasmic reticulum (SR) was studied by means of different approaches, such as enzyme activity, fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and molecular docking simulations. The ATP hydrolysis activity was fully inhibited by incubation with dirhamnolipid (diRL) up to 0.1 mM concentration, corresponding to a surfactant concentration below membrane solubilization threshold. Surfactant-protein interaction induced conformational changes in the protein observed by an increase in the accessibility of tryptophan residues to the aqueous phase and by changes in the secondary structure of the protein as seen by fluorescence and FTIR spectroscopy. As a consequence, the protein become more unstable and denatured at lower temperatures, as seen by enzyme activity and DSC studies. Finally, these results were explained at molecular level throughout molecular docking simulations. It is concluded that there is a specific dirhamnolipid-protein interaction not related to the surface activity of the surfactant but to the particular physicochemical properties of the biosurfactant molecule.

Reusable Low-Cost 3D Training Model for Aneurysm Clipping.

BACKGROUND: Aneurysm clipping requires the proficiency of several skills, yet the traditional way of practicing them has been recently challenged, especially by the growth of endovascular techniques. The use of simulators could be an alternative educational tool, but some of them are cumbersome, expensive to implement, or lacking in realism. The aim of this study is to evaluate a reusable low-cost 3-dimensional printed training model we developed for aneurysm clipping. METHODS: The simulator was designed to replicate the bone structure, arteries, and targeted aneurysms. Thirty-two neurosurgery residents performed a craniotomy and aneurysm clipping using the model and then filled out a survey. They were divided into Junior and Senior groups. Descriptive, exploratory, and confirmatory factor analysis was performed using IBM SPSS statistical software. RESULTS: The overall residents' response was positive, with high scores to face validity and content validity questions. There was no significant statistical difference between the Junior and Senior groups. The confirmatory factor and internal consistency analysis confirmed that the evaluation was highly reliable. Globally, 97% of the residents found the model was useful and would repeat the simulator experience. The financial cost is $2500 USD for implementation and only $180 USD if further training sessions are required. CONCLUSIONS: The main strengths of our training model are its highlighted realism, adaptability to trainees of different levels of expertise, sustainability, and low cost. Our data support the concept that it can be incorporated as a new training opportunity during professional specialty meetings and/or within residency academic programs.

Breast metastasis from medullary thyroid carcinoma mimicking ductal carcinoma with neuroendocrine differentiation.

BACKGROUND: Medullary thyroid carcinoma very rarely metastasizes to the breast. Hematogenous spread to the liver, lungs, or mediastinum is more common. CASE: We describe the morphologic and immunohistochemical features of a 63-year-old woman who presented with a BIRADS-5 category nodule in the right breast and enlarged axillary lymph nodes. Core biopsy showed suggested breast cancer with neuroendocrine or apocrine differentiation. The immunohistochemical profile showed (RE-/RP-/HER-2-) and Ki67 10%. Chromogranin and synaptophysin were positive; AR and GCDFP-15 were negative. On reviewing the patient's clinical history, it was discovered that she had been treated for medullary thyroid carcinoma 15 years earlier. Additional stains showed positivity for TTF-1, CEA, and calcitonin. These findings were consistent with a diagnosis of breast metastasis from medullary thyroid carcinoma. We discuss briefly the morphologic features and the possible key features in order to make an accurate diagnosis. CONCLUSION: This case highlights the importance of investigating a history of cancer in patients with discordant or unusual histologic or immunohistochemical findings, as this can help avoid misdiagnosis and inappropriate treatment.

Effect of a dirhamnolipid biosurfactant on the structure and phase behaviour of dimyristoylphosphatidylserine model membranes.

Rhamnolipids are bacterial biosurfactants containing one or two rhamnose rings and a hydrophobic hydrocarbon portion. These compounds are mainly isolated from Pseudomonas spp culture media, and have been shown to present outstanding biological activities. A number of experimental works have shown that the interaction of rhamnolipids with target membranes could play a role in these actions. Therefore the study of the interaction of purified rhamnolipids with the various phospholipid components of biological membranes is of great interest. This paper shows the phase behaviour of mixtures of 1,2-dimyristolylphosphatidylserine (DMPS) with a dirhamnolipid (diRL) fraction produced by P. aeruginosa. This experimental approach has been based on the use of physical techniques such as Differential Scanning Calorimetry (DSC) and Fourier-Transform Infrared Spectroscopy (FTIR). DSC indicated that the presence of increasing concentrations of diRL in the bilayer resulted in a progressive broadening of the gel to liquid-crystalline phase transition of DMPS. In addition a complex thermal behaviour was observed, with the presence of more than one transition at higher concentrations of the biosurfactant, indicating phase separation. FTIR showed that diRL increased the proportion of gauche rotamers of DMPS, thus affecting acyl chain order. The change in the frequency of the carboxylate stretching band of DMPS observed upon interaction with diRL pointed toward changes in the local environment of the polar headgroup of the phospholipid, resulting in a modification of its conformation or insertion within the bilayer. This result was corroborated by the effect of diRL on the carbonyl and phosphate stretching bands of DMPS, showing an increase of the hydration both in the gel and in the liquid-crystalline phase. Molecular Dynamics (MD) simulations gave further support to the experimental results, showing diRL cluster formation as well as an augmented exposition of DMPS to the water layer in the presence of the biosurfactant.

Optimization of Innovative Three-Dimensionally-Structured Hybrid Vesicles to Improve the Cutaneous Delivery of Clotrimazole for the Treatment of Topical Candidiasis.

New three-dimensionally-structured hybrid phospholipid vesicles, able to load clotrimazole in a high amount (10 mg/mL), were obtained for the first time in this work by significantly reducing the amount of water (≤10%), which was replaced with a mixture of glycerol and ethanol (≈90%). A pre-formulation study was carried out to evaluate the effect of both the composition of the hydrating medium and the concentration of the phospholipid on the physico-chemical properties of hybrid vesicles. Four different three-dimensionally-structured hybrid vesicles were selected as ideal systems for the topical application of clotrimazole. An extensive physico-chemical characterization performed using transmission electron microscopy (TEM), cryogenic transmission electron microscopy (cryo-TEM), 31P-NMR, and small-angle X-ray scattering (SAXS) displayed the formation of small, multi-, and unilamellar vesicles very close to each other, and was capable of forming a three-dimensional network, which stabilized the dispersion. Additionally, the dilution of the dispersion with water reduced the interactions between vesicles, leading to the formation of single unilamellar vesicles. The evaluation of the in vitro percutaneous delivery of clotrimazole showed an improved drug deposition in the skin strata provided by the three-dimensionally-structured vesicles with respect to the commercial cream (Canesten®) used as a reference. Hybrid vesicles were highly biocompatible and showed a significant antifungal activity in vitro, greater than the commercial cream Canesten®. The antimycotic efficacy of formulations was confirmed by the reduced proliferation of the yeast cells at the site of infection in vivo. In light of these results, clotrimazole-loaded, three-dimensionally-structured hybrid vesicles appear to be one of the most innovative and promising formulations for the treatment of candidiasis infections.

Per oral endoscopic myotomy in a pediatric patient with achalasia. / Miotomía endoscópica por vía oral (POEM) en un paciente pediátrico para tratamiento de la acalasia esofágica.

INTRODUCTION: Achalasia is the most common primary motor disorder of the esophagus. Its reported incidence is low, even more in pediatric patients. Laparoscopic Heller myotomy is the current stan dard of treatment. During the last years, per-oral endoscopic myotomy (POEM) has been positioned as a safe and effective therapeutic alternative as the Heller procedure for esophageal achalasia. Ob jective: To describe the POEM technique and report the first pediatric case in our country. CLINICAL CASE: 11-year-old patient, previously healthy, who presented with progressive dysphagia for solids and liquids and weight loss. The study concluded a type II achalasia. The patient underwent a POEM and had a postoperative course without incidents. One year after the intervention, symptomatic, endoscopic and manometric resolution have been documented. CONCLUSIONS: The described case is the first POEM in a pediatric patient in our country. Esophageal achalasia is uncommon in pediatrics and POEM has demonstrated clinical success and safety comparable to laparoscopic Heller myotomy in short and medium term. Long-term follow-up will determine its definitive role in the treatment of pediatric patients with esophageal achalasia.

Miotomía endoscópica por vía oral (POEM) en un paciente pediátrico para tratamiento de la acalasia esofágica / Per oral endoscopic myotomy in a pediatric patient with achalasia

INTRODUCCIÓN: La acalasia es el trastorno motor primario más frecuente del esófago. Su incidencia reportada es baja, aún más en pacientes pediátricos. La miotomía de Heller laparoscópica corresponde al estándar actual de tratamiento. Durante los últimos años la miotomía endoscópica por vía oral (POEM) se ha posicionado como una alternativa terapéutica segura y tan efectiva como el Heller para la acalasia esofágica. OBJETIVO: Describir la técnica de POEM y reportar el primer caso pediátrico en nuestro país. CASO CLÍNICO: Paciente de 11 años, previamente sano, que se presentó con disfagia ilógica progresiva y baja de peso. El estudio concluyó una acalasia tipo II. Fue sometido a POEM y cursó un postoperatorio sin incidentes. A un año de la intervención se ha documentado resolución de la sintomatología, seguimiento endoscópico y manométrico sin complicaciones. CONCLUSIONES: El caso descrito corresponde al primer POEM en un paciente pediátrico en nuestro país. La acalasia esofágica es infrecuente en pediatría y el POEM ha demostrado éxito clínico y seguridad comparables a la miotomía de Heller laparoscópica en el corto y mediano plazo. El seguimiento a largo plazo permitirá determinar su rol definitivo en el tratamiento de pacientes pediátricos con acalasia esofágica.

INTRODUCTION: Achalasia is the most common primary motor disorder of the esophagus. Its reported incidence is low, even more in pediatric patients. Laparoscopic Heller myotomy is the current stan dard of treatment. During the last years, per-oral endoscopic myotomy (POEM) has been positioned as a safe and effective therapeutic alternative as the Heller procedure for esophageal achalasia. OBJECTIVE: To describe the POEM technique and report the first pediatric case in our country. CLINICAL CASE: 11-year-old patient, previously healthy, who presented with progressive dysphagia for solids and liquids and weight loss. The study concluded a type II achalasia. The patient underwent a POEM and had a postoperative course without incidents. One year after the intervention, symptomatic, endoscopic and manometric resolution have been documented. CONCLUSIONS: The described case is the first POEM in a pediatric patient in our country. Esophageal achalasia is uncommon in pediatrics and POEM has demonstrated clinical success and safety comparable to laparoscopic Heller myotomy in short and medium term. Long-term follow-up will determine its definitive role in the treatment of pediatric patients with esophageal achalasia.

Parallel sorting of orbital and spin angular momenta of light in a record large number of channels.

Parallel sorting of orbital and spin angular momentum components of structured optical beams is demonstrated. Both spin channels are multiplexed within the novel orbital angular momentum (OAM) sorter, reducing the size, weight, and number of elements. The sorted states are linearly spaced over 70 topological charge values. We experimentally and theoretically evaluate the operational range and crosstalk between neighboring channels and find that 30 orbital angular momentum states are available per spin channel for quantum communication or cryptography. This is achieved using an angular momentum sorter that we developed based on geometric phase optical elements. We present two devices consisting of liquid crystal polymer films photoaligned with complex two-dimensional patterns.

Nanodesign of new self-assembling core-shell gellan-transfersomes loading baicalin and in vivo evaluation of repair response in skin.

Gellan nanohydrogel and phospholipid vesicles were combined to incorporate baicalin in new self-assembling core-shell gellan-transfersomes obtained by an easy, scalable method. The vesicles were small in size (~107 nm) and monodispersed (P.I. ≤ 0.24), forming a viscous system (~24 mPa/s) as compared to transfersomes (~1.6 mPa/s), as confirmed by rheological studies. Gellan was anchored to the bilayer domains through cholesterol, and the polymer chains were distributed onto the outer surface of the bilayer, thus forming a core-shell structure, as suggested by SAXS analyses. The optimal carrier ability of core-shell gellan-transfersomes was established by the high deposition of baicalin in the skin (~11% in the whole skin), especially in the deeper tissue (~8% in the dermis). Moreover, their ability to improve baicalin efficacy in anti-inflammatory and skin repair tests was confirmed in vivo in mice, providing the complete skin restoration and inhibiting all the studied inflammatory markers.