Structural, chemical, and magnetic investigation of a graphene/cobalt/platinum multilayer system on silicon carbide.

We investigate the magnetic interlayer coupling and domain structure of ultra-thin ferromagnetic (FM) cobalt (Co) layers embedded between a graphene (G) layer and a platinum (Pt) layer on a silicon carbide (SiC) substrate (G/Co/Pt on SiC). Experimentally, a combination of x-ray photoemission electron microscopy with x-ray magnetic circular dichroism has been carried out at the Co L-edge. Furthermore, structural and chemical properties of the system have been investigated using low energy electron diffraction (LEED) and x-ray photoelectron spectroscopy (XPS).In situLEED patterns revealed the crystalline structure of each layer within the system. Moreover, XPS confirmed the presence of quasi-freestanding graphene, the absence of cobalt silicide, and the appearance of two silicon carbide surface components due to Pt intercalation. Thus, the Pt-layer effectively functions as a diffusion barrier. The magnetic structure of the system was unaffected by the substrate's step structure. Furthermore, numerous vortices and anti-vortices were found in all samples, distributed all over the surfaces, indicating Dzyaloshinskii-Moriya interaction. Only regions with a locally increased Co-layer thickness showed no vortices. Moreover, unlike in similar systems, the magnetization was predominantly in-plane, so no perpendicular magnetic anisotropy was found.

Validation of a novel testing machine for the investigation of the biomechanical properties of lumbar vertebrae in an osteoporotic rat model.

BACKGROUND: For the investigation of the biomechanical properties of bone, various testing devices have been described. However, only a limited number have been developed to test the vertebral body of small animals. The aim of this study was to develop and validate a new bone testing device, which investigates the different biomechanical properties in small-animal vertebrae as a whole, three-dimensional unit, respecting its anatomical structure. METHODS: Thirty-five twelve-week-old female Sprague Dawley rats were utilized. Group 1 was composed of 17 rats with a normal bone metabolism without osteoporosis, while Group 2 consisted of 18 rats with manifest osteoporosis, 8 weeks after ovariectomy. The 5th lumbar vertebra of each animal was tested using the new bone testing device. This device has the ability to be adjusted to the slanted nature of each individual vertebral body and fix the vertebra in a natural position to allow for a non-dislocating axial force application. The device is designed to respect the anatomical three-dimensional shape of the vertebral body, thus avoiding the application of non-anatomic, non-physiological forces and thus preventing a distortion of the biomechanical testing results. The parameters investigated were stiffness, yield load, maximum load and failure load, and the results were compared to current literature values. RESULTS: The conduction of the biomechanical bone testing of the vertebral bodies with the new device was conductible without any instances of dislocation of the vertebrae or machine malfunctions. Significant differences were found for stiffness, maximum load and failure load between groups, with a lower value in the osteoporotic rats in each parameter tested. The yield load was also lower in the osteoporotic group, however not significantly. The values achieved correlate with those in current literature. CONCLUSIONS: This study demonstrates that the newly developed testing machine is easy to handle and produces valid data sets for testing biomechanical bone parameters of whole vertebral bodies in an established small animal model. Therefore, it can be utilized, also as reference data, to test different structural properties and changes in vertebral bone, for example, in different metabolic settings or under the influence of different pharmaceutical entities in further studies.

The role of executive functions, social cognition and intelligence in predicting social adaptation of vulnerable populations.

This study sought to evaluate the roles of and interactions between cognitive processes that have been shown to exhibit impact from socioeconomic status (SES) and living conditions in predicting social adaptation (SA) in a population of adults living in socially vulnerable conditions. Participants included 226 people between the ages of 18 and 60 who have been living in vulnerable contexts throughout life in Santiago, Chile. Data was collected through a battery of psychological assessments. A structural equation model (SEM) was implemented to examine the interrelationships among cognitive and social variables. Results indicate a significant relationship between executive function (EF) and SA through both social cognition (SC) and intelligence. Theory of Mind (ToM), a component of SC, was shown to exhibit a significant relationship with affective empathy; interestingly, this was negatively related to SA. Moreover, fluid intelligence (FI) was found to exhibit a positive, indirect relationship with SA through crystallized intelligence (CI). Evaluation of these results in the context of research on the impacts of SES and vulnerable living conditions on psychological function may allow for the development of more effective clinical, political, and social interventions to support psychosocial health among socially vulnerable populations.

How Softness Matters in Soft Nanogels and Nanogel Assemblies.

Softness plays a key role in determining the macroscopic properties of colloidal systems, from synthetic nanogels to biological macromolecules, from viruses to star polymers. However, we are missing a way to quantify what the term "softness" means in nanoscience. Having quantitative parameters is fundamental to compare different systems and understand what the consequences of softness on the macroscopic properties are. Here, we propose different quantities that can be measured using scattering methods and microscopy experiments. On the basis of these quantities, we review the recent literature on micro- and nanogels, i.e. cross-linked polymer networks swollen in water, a widely used model system for soft colloids. Applying our criteria, we address the question what makes a nanomaterial soft? We discuss and introduce general criteria to quantify the different definitions of softness for an individual compressible colloid. This is done in terms of the energetic cost associated with the deformation and the capability of the colloid to isotropically deswell. Then, concentrated solutions of soft colloids are considered. New definitions of softness and new parameters, which depend on the particle-to-particle interactions, are introduced in terms of faceting and interpenetration. The influence of the different synthetic routes on the softness of nanogels is discussed. Concentrated solutions of nanogels are considered and we review the recent results in the literature concerning the phase behavior and flow properties of nanogels both in three and two dimensions, in the light of the different parameters we defined. The aim of this review is to look at the results on micro- and nanogels in a more quantitative way that allow us to explain the reported properties in terms of differences in colloidal softness. Furthermore, this review can give researchers dealing with soft colloids quantitative methods to define unambiguously which softness matters in their compound.

Microgels react to force: mechanical properties, syntheses, and force-activated functions.

Microgels are colloidal polymer networks with high molar mass and properties between rigid particles, flexible macromolecules, and micellar aggregates. Their unique stimuli-responsiveness in conjunction with their colloidal phase behavior render them useful for many applications ranging from engineering to biomedicine. In many scenarios either the microgel's mechanical properties or its interactions with mechanical force play an important role. Here, we firstly explain microgel mechanical properties and how these are measured by atomic force microscopy (AFM), then we equip the reader with the synthetic background to understand how specific architectures and chemical functionalities enable these mechanical properties, and eventually we elucidate how the interaction of force with microgels can lead to the activation of latent functionality. Since the interaction of microgels with force is a multiscale and multidisciplinary subject, we introduce and interconnect the different research areas that contribute to the understanding of this emerging field in this Tutorial Review.

Stiffness Tomography of Ultra-Soft Nanogels by Atomic Force Microscopy.

The softness of nanohydrogels results in unique properties and recently attracted tremendous interest due to the multi-functionalization of interfaces. Herein, we study extremely soft temperature-sensitive ultra-low cross-linked (ULC) nanogels adsorbed to the solid/water interface by atomic force microscopy (AFM). The ultra-soft nanogels seem to disappear in classical imaging modes since a sharp tip fully penetrates these porous networks with very low forces in the range of steric interactions (ca. 100 pN). However, the detailed evaluation of Force Volume mode measurements allows us to resolve their overall shape and at the same time their internal structure in all three dimensions. The nanogels exhibit an extraordinary disk-like and entirely homogeneous but extremely soft structure-even softer than polymer brushes. Moreover, the temperature-sensitive nanogels can be switched on demand between the ultra-soft and a very stiff state.

Influence of burn severity on endothelial glycocalyx shedding following thermal trauma: A prospective observational study.

OBJECTIVE: Severe burns cause hypermetabolic and inflammatory responses are treated with significant volume resuscitation. This study aimed to evaluate correlations between glycocalyx metabolites and the burn size as well as certain clinical parameters such as administered fluid volumes. STUDY DESIGN: Severely burned patients with a total body surface area (TBSA) burned smaller and larger than 20% were included. Clinical parameters including length of stay, mortality, fluid administration and Sequential Organ Failure Assessment (SOFA) score as well as syndecan and heparansulfate, as laboratory parameters for endothelial damage, were obtained. RESULTS: A total of 39 patients (32 males, 7 females) with a mean age at burn of 45 ± 21 years were included. Syndecan levels decreased and heparansulfate levels increased over time. In both heparansulfate and syndecan, there was no significant difference between burns smaller and larger than 20% TBSA at any time point. Syndecan levels at 24 h after burn correlated significantly with IL-10 levels at admission (R = 0.58 and p < 0.05). There were significant linear correlations of %TBSA and cumulative administration of fluids after 24 h on syndecan levels after 48 h. Correlations between clinical parameters and syndecan or heparansulfate levels over time were not found. CONCLUSIONS: This study shows that even though there are moderate correlations with burn size and administered fluid volume, levels of syndecan and heparansulfate are not predictive for clinical outcomes of burned patients in our cohort. Further studies with higher numbers evaluating the effect of large burns on glycocalyx shedding over a longer period of time are needed. Showing significant glycocalyx shedding in large burn including potentially correlations with clinical outcomes may yield new therapeutic targets.

Phase behavior of ultrasoft spheres show stable bcc lattices.

The phase behavior of supersoft spheres is explored using solutions of ultralow cross-linked poly(N-isopropylacrylamide)-based microgels as a model system. For these microgels, the effects of the electric charges on their surfaces can be neglected and therefore only the role of softness on the phase behavior is investigated. The samples show a liquid-to-crystal transition at higher volume fraction with respect to both hard spheres and stiffer microgels. Furthermore, stable body centered cubic (bcc) crystals are observed in addition to the expected face centered cubic (fcc) crystals. Small-angle x-ray and neutron scattering with contrast variation allow the characterization of both the microgel-to-microgel distance and the architecture of single microgels in crowded solutions. The measurements reveal that the stable bcc crystals depend on the interplay between the collapse and the interpenetration of the external shell of the ultralow cross-linked microgels.

Characterizing membrane phospholipid hydrolysis of pork loins throughout three aging periods.

Three chops from 20 pork carcasses were aged for 1, 8, and 21 days. Electrospray ionization-tandem mass spectrometry was used to comprehensively analyze profiles of phospholipids from each sample (n = 60). Total phospholipid quantity decreased 4-folds (P < .01) from 1 to 21 days of aging in pork loins. Phosphatidylinositol (PI) and phosphatidylserine (PS) increased by 30% and 73%, respectively, from 1 to 21 days of aging in pork loins (P < .01). This increase was mainly due to relative percentage increase from PI 38:4 (18:0-20:4) and PS 36:2 (18:0-18:2; P < .01). The results also showed that the relative percentage of lysophosphatidylcholine increased by 35% after short term aging (8d), and phosphatidic acid increased by 10-folds after extended aging (21d; P < .01). These results documented that phospholipids undergo enzymatic hydrolysis during aging, but also indicated that lipid species containing 18:2 or 20:4 within PI and PS were slightly more resistant to enzymatic hydrolysis compared with the other phospholipids.

Effect of the 3D Swelling of Microgels on Their 2D Phase Behavior at the Liquid-Liquid Interface.

We investigate soft, temperature-sensitive microgels at fluid interfaces. Though having an isotropic, spherical shape in bulk solution, the microgels become anisotropic upon adsorption. The structure of microgels at interfaces is described by a core-corona morphology. Here, we investigate how changing temperature across the microgel volume phase transition temperature, which leads to swelling/deswelling of the microgels in the aqueous phase, affects the phase behavior within the monolayer. We combine compression isotherms, atomic force microscopy imaging, multiwavelength ellipsometry, and computer simulations. At low compression, the interaction between adsorbed microgels is dominated by their highly stretched corona and the phase behavior of the microgel monolayers is the same. The polymer segments within the interface lose their temperature-sensitivity because of the strong adsorption to the interface. At high compression, however, the portions of the microgels that are located in the aqueous side of the interface become relevant and prevail in the microgel interactions. These portions are able to collapse and, consequently, the isostructural phase transition is altered. Thus, the temperature-dependent swelling perpendicular to the interface ("3D") affects the compressibility parallel to the interface ("2D"). Our results highlight the distinctly different behavior of soft, stimuli-sensitive microgels as compared to rigid nanoparticles.

Tuning the Structure and Properties of Ultra-Low Cross-Linked Temperature-Sensitive Microgels at Interfaces via the Adsorption Pathway.

The structure of poly(N-isopropylacrylamide) (PNIPAM) microgels adsorbed onto a solid substrate is investigated in the dry and hydrated states by means of atomic force microscopy (AFM). We compare two different systems: a regularly cross-linked microgel containing 5 mol % cross-linker and ultra-low cross-linked microgels (ULC) prepared without a dedicated cross-linker. Furthermore, we compare three different adsorption processes: (i) in situ adsorption from solution, (ii) spin-coating, and (iii) Langmuir-Blodgett deposition from an oil-water interface. The results demonstrate that the morphology and the temperature-induced collapse of microgels adsorbed onto a solid substrate are very different for ultra-low cross-linked microgels as compared to regularly cross-linked microgels, despite the fact that their general behavior in solution is very similar. Furthermore, the morphology of ULC microgels can be controlled by the adsorption pathway onto the substrate. Absorbed ULC microgels are strongly deformed when being prepared either by spin-coating or by Langmuir-Blodgett deposition from an oil-water interface. After rehydration, the ULC microgels cannot collapse as entire objects, instead small globules are formed. Such a strong deformation can be avoided by in situ adsorption onto the substrate. Then, the ULC microgels exhibit half-ellipsoidal shapes with a smooth surface in the collapsed state similar to the more cross-linked microgels. As ULC microgels can be selectively trapped either in a more particle-like or in a more polymer-like behavior, coatings with strongly different topographies and properties can be prepared by one and the same ultra-low cross-linked microgel. This provides new opportunities for the development of smart polymeric coatings.

Impact of body mass index on 30-day postoperative morbidity in pediatric and adolescent patients undergoing continent urinary tract reconstruction.

INTRODUCTION: Obesity has been thought to increase the risk of complications and need for additional resources with surgery, but only a limited amount of evidence is available in the pediatric population. OBJECTIVE: The objectives were to describe the weight status of pediatric and adolescent patients undergoing a continent urinary tract reconstruction and to determine the association between obesity and 30-day postoperative morbidity. STUDY DESIGN: A retrospective cohort study was performed for pediatric and adolescent patients aged up to 20 years who underwent a continent urinary tract reconstruction between January 2010 and November 2016. Weight status was stratified by the body mass index (BMI) for age z-scores as follows: underweight (<5th percentile), normal (5th to <85th percentiles), overweight (85th to <95th percentiles), and obese (≥95th percentile). Primary outcomes included the duration of intensive care and hospitalization as well as re-admissions and complications within 30 days. RESULTS: A total of 182 continent reconstructions were identified during the study period. Demographic and peri-operative data are provided in the Table. Weight status was not associated with any primary outcomes on univariate or multivariate analysis. There was also no association in an analysis between the non-overweight or non-obese group (BMI for age z-score <85th) and overweight or obese group (BMI for age z-score ≥85th percentiles); a subgroup analysis between patients with and without myelomeningocele; or a subgroup analysis for wound, infectious, or high-grade (Clavien-Dindo grades III or higher) complications. DISCUSSION: Obesity has been consistently associated with an increased risk of surgical site infections and wound complications after a wide variety of surgeries in adults. The results from the present study conflict with those of the few available studies in the pediatric population. The high-risk nature of the present cohort may have mitigated any effect of obesity on 30-day postoperative morbidity. The limitations of the present study include its retrospective design at a single center and the potential misclassification of weight status with the BMI. CONCLUSIONS: Almost 30% of pediatric and adolescent patients undergoing a continent urinary tract reconstruction were overweight or obese. Obesity as determined by the BMI was not associated with 30-day postoperative morbidity.

Exploring the colloid-to-polymer transition for ultra-low crosslinked microgels from three to two dimensions.

Microgels are solvent-swollen nano- and microparticles that show prevalent colloidal-like behavior despite their polymeric nature. Here we study ultra-low crosslinked poly(N-isopropylacrylamide) microgels (ULC), which can behave like colloids or flexible polymers depending on dimensionality, compression or other external stimuli. Small-angle neutron scattering shows that the structure of the ULC microgels in bulk aqueous solution is characterized by a density profile that decays smoothly from the center to a fuzzy surface. Their phase behavior and rheological properties are those of soft colloids. However, when these microgels are confined at an oil-water interface, their behavior resembles that of flexible macromolecules. Once monolayers of ultra-low crosslinked microgels are compressed, deposited on solid substrate and studied with atomic-force microscopy, a concentration-dependent topography is observed. Depending on the compression, these microgels can behave as flexible polymers, covering the substrate with a uniform film, or as colloidal microgels leading to a monolayer of particles.

Robust and Resource-Efficient Microwave Near-Field Entangling

Microwave trapped-ion quantum logic gates avoid spontaneous emission as a fundamental source of decoherence. However, microwave two-qubit gates are still slower than laser-induced gates and hence more sensitive to fluctuations and noise of the motional mode frequency. We propose and implement amplitude-shaped gate drives to obtain resilience to such frequency changes without increasing the pulse energy per gate operation. We demonstrate the resilience by noise injection during a two-qubit entangling gate with ^{9}Be^{+} ion qubits. In the absence of injected noise, amplitude modulation gives an operation infidelity in the 10^{-3} range.

Preoperative nutritional status and use of total parenteral nutrition in pediatric and adolescent patients undergoing continent urinary tract reconstruction.

INTRODUCTION: A nutritional assessment is a critical but often neglected aspect of a preoperative evaluation. Malnutrition is clearly associated with worse surgical outcomes in adults undergoing major abdominal surgery, whereas a paucity of evidence is available in the pediatric population. OBJECTIVE: The objectives were to describe the preoperative nutritional status of pediatric and adolescent patients undergoing continent urinary tract reconstruction and to determine the association among malnutrition, use of total parenteral nutrition (TPN), and surgical outcomes. STUDY DESIGN: A retrospective cohort study was performed for patients aged up to 20 years who underwent continent urinary tract reconstruction between January 2012 and November 2016. Malnutrition was classified with body mass index and height for age z-scores on admission as well as change in z-scores and weight over the 3-6 months before surgery. Primary outcomes included the duration of intensive care and hospitalization as well as readmissions and complications within 30 days. RESULTS: A total of 123 patients who underwent 130 continent urinary tract reconstructions were identified during the study period. Demographic and perioperative data are provided in the Table. Anthropometric and biochemical measurements as well as the early initiation of TPN (≤2 days) were not associated with any primary outcomes. In a subgroup analysis of patients with a bowel anastomosis, the early initiation of TPN was an independent predictor for duration of hospitalization (P < 0.0001) and 30-day complications (odds ratio 9.51, P = 0.005) after adjusting for other statistically significant and clinically relevant variables. DISCUSSION: The few available studies on surgical nutrition have primarily focused on infants and young children undergoing cardiac surgery and provided no consensus on a preoperative nutritional assessment. The findings on TPN from the present study favorably compare with a growing body of evidence in adult and pediatric critically ill and surgical patients. The limitations of the present study include its retrospective design at a single institution, potential misclassification of nutritional status, and selection bias from the initiation of TPN at the discretion of the primary surgeon. CONCLUSIONS: Malnutrition was identified in greater than 20% of pediatric and adolescent patients undergoing continent urinary tract reconstruction. Anthropometric and biochemical parameters were not associated with surgical outcomes, although the early initiation of TPN did not offer any benefit for nutritional support. In a subset of patients with a bowel anastomosis, TPN was associated with worse surgical outcomes, including a longer duration of hospitalization and development of 30-day complications.

The relation between gray matter volume and the use of alcohol, tobacco, cocaine and cannabis in male polysubstance users.

BACKGROUND: Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use. METHODS: In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine. RESULTS: Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively. CONCLUSION: These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders.

Probing the Internal Heterogeneity of Responsive Microgels Adsorbed to an Interface by a Sharp SFM Tip: Comparing Core-Shell and Hollow Microgels.

Microgels composed of thermoresponsive polymer poly( N-isopropylacrylamide) (PNIPAM) are interfacial active. Their adsorption leads to deformation, causing conformational changes that have profound effects on the macroscopic properties of these films. Yet, methods to quantitatively probe the local density are lacking. We introduced scanning force microscopy (SFM) to quantitatively probe the internal structure of microgels physically adsorbed on a solid (SiO2)/water interface. Using a sharp SFM tip, we investigated the two types of microgels: (i) core-shell microgels featuring a hard silica core and a PNIPAM shell and (ii) hollow microgels obtained by dissolution of the silica core. Thus, both systems have the same polymer network as the peripheral structure but a distinctly different internal structure, that is, a rigid core versus a void. By evaluating the force-distance curves, the force profile during insertion of the tip into the polymer network enables to determine a depth-dependent contact resistance, which closely correlates with the density profiles determined in solution by small-angle neutron scattering. We found that the cavity of the swollen hollow microgels is still present when adsorbed to the solid substrate. Remarkably, while currently used techniques such as colloidal probe or reflectometry only provide an average of the z-profile, the methodology introduced herein actually probes the real three-dimensional density profile, which is ultimately important to understand the macroscopic behavior of microgel films. This will bridge the gap between the colloidal probe experiments that deform the microgel globally and the insertion in which the disturbance is located near the tip.

Preliminary report: Surgical outcomes following genitoplasty in children with moderate to severe genital atypia.

INTRODUCTION: Prior studies of outcomes following genitoplasty have reported high rates of surgical complications among children with atypical genitalia. Few studies have prospectively assessed outcomes after contemporary surgical approaches. OBJECTIVE: The current study reported the occurrence of early postoperative complications and of cosmetic outcomes (as rated by surgeons and parents) at 12 months following contemporary genitoplasty procedures in children born with atypical genitalia. STUDY DESIGN: This 11-site, prospective study included children aged ≤2 years, with Prader 3-5 or Quigley 3-6 external genitalia, with no prior genitoplasty and non-urogenital malformations at the time of enrollment. Genital appearance was rated on a 4-point Likert scale. Paired t-tests evaluated differences in cosmesis ratings. RESULTS: Out of 27 children, 10 were 46,XY patients with the following diagnoses: gonadal dysgenesis, PAIS or testosterone biosynthetic defect, severe hypospadias and microphallus, who were reared male. Sixteen 46,XX congenital adrenal hyperplasia patients were reared female and one child with sex chromosome mosaicism was reared male. Eleven children had masculinizing genitoplasty for penoscrotal or perineal hypospadias (one-stage, three; two-stage, eight). Among one-stage surgeries, one child had meatal stenosis (minor) and one developed both urinary retention (minor) and urethrocutaneous fistula (major) (Summary Figure). Among two-stage surgeries, three children developed a major complication: penoscrotal fistula, glans dehiscence or urethral dehiscence. Among 16 children who had feminizing genitoplasty, vaginoplasty was performed in all, clitoroplasty in nine, external genitoplasty in 13, urethroplasty in four, perineoplasty in five, and total urogenital sinus mobilization in two. Two children had minor complications: one had a UTI, and one had both a mucosal skin tag and vaginal mucosal polyp. Two additional children developed a major complication: vaginal stenosis. Cosmesis scores revealed sustained improvements from 6 months post-genitoplasty, as previously reported, with all scores reported as good or satisfied. DISCUSSION: In these preliminary data from a multi-site, observational study, parents and surgeons were equally satisfied with the cosmetic outcomes 12 months after genitoplasty. A small number of patients had major complications in both feminizing and masculinizing surgeries; two-stage hypospadias repair had the most major complications. Long-term follow-up of patients at post-puberty will provide a better assessment of outcomes in this population. CONCLUSION: In this cohort of children with moderate to severe atypical genitalia, preliminary data on both surgical and cosmetic outcomes were presented. Findings from this study, and from following these children in long-term studies, will help guide practitioners in their discussions with families about surgical management.

Allosteric modulation of α4ß2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain.

BACKGROUND: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The α4ß2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of α4ß2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for α4ß2 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at α4ß2 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine-induced antinociception. METHODS: The present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotine-evoked antiallodynic response. RESULTS: We found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour dose- and time-dependently without motor impairment. Our data revealed that this effect was mediated by the α4ß2 nAChRs by using competitive α4ß2 antagonist dihydro-ß-erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to α4ß2 nAChRs. CONCLUSIONS: The present results suggest that allosteric modulation of α4ß2 nAChR may provide new strategies in chronic neuropathic pain. SIGNIFICANCE: α4ß2 nAChRs are involved in pain modulation. dFBr, a PAM at α4ß2 nAChRs, potentiates the nicotine response dose-dependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of α4ß2* nAChR may provide new strategies in chronic neuropathic pain.