The melting of glucose.

Several sugars are known to undergo a spontaneous liquefaction below their reputed melting point (Tm), but the origin of this apparent melting is not yet clearly understood. In this paper we address this puzzling behavior in the particular case of the crystalline forms of glucose: Gα and Gß, involving respectively the glucose-α and glucose-ß anomers. We show in particular that the spontaneous melting below their reputed melting point Tm (∼151 °C for Gα and ∼156 °C for Gß) corresponds to a horizontal displacement of the system in the eutectic phase diagram of the anomeric mixture glucose-α / glucose-ß. This displacement is associated with mutarotation in the liquid which, in turn, induces additional liquefaction of the remaining crystal. This feedback loop creates a vicious circle which stops when the mixture reaches the liquidus branch, i.e. when the liquefaction is total. It is also shown that this behavior becomes more complex on approaching the eutectic temperature Te (120 °C). Just above Te, the liquefaction process is followed by a recrystallization leading to the crystalline form Gß. On the other hand, just below Te, the spontaneous liquefaction process stops as no melting is expected whatever the anomeric composition.

Paris MEM: a study protocol for an effectiveness and efficiency trial on the treatment of traumatic stress in France after the 2015-16 terrorist attacks.

BACKGROUND: The Paris and Nice terrorist attacks affected a thousand of trauma victims and first-line responders. Because there were concerns that this might represent the first of several attacks, there was a need to quickly enhance the local capacities to treat a large number of individuals suffering from trauma-related disorders. Since Reconsolidation Therapy (RT) is brief, relatively easy to learn, well tolerated and effective, it appeared as the ideal first-line treatment to teach to clinicians in this context. METHODS: This study protocol is a two-arm non-randomized, multicenter controlled trial, comparing RT to treatment as usual for the treatment of trauma-related disorders. RT consists of actively recalling one's traumatic event under the influence of the ß-blocker propranolol, once a week, for 10-25 min with a therapist, over 6 consecutive weeks. This protocol evaluates the feasibility, effectiveness, and cost-utility of implementing RT as part of a large multi-center (N = 400) pragmatic trial with a one-year follow-up. DISCUSSION: Paris MEM is the largest trial to date assessing the efficiency of RT in the aftermath of a large-scale man-made disaster. RT could possibly reinforce the therapeutic arsenal for the treatment of patients suffering from trauma-related disorders, not only for communities in western countries but also worldwide for terror- or disaster-stricken communities. TRIAL REGISTRATION: Clinical Trials (ClinicalTrials.gov). June 3, 2016. NCT02789982.

Feather pecking in laying hens housed in free-range or furnished-cage systems on French farms.

1. Beak trimming is currently used in France to avoid the negative consequences of severe feather pecking (SFP). However, this practice is controversial in terms of animal welfare, and forbidden in some European countries.2. This study aimed to assess the prevalence of SFP in French laying hen farms, to describe how farmers manage this behavioural disorder and to better understand the risk factors involved.3. A study was carried out from April 2015 to June 2016. Visits were paid to 79 flocks kept in furnished cages (FC) and 80 flocks in a free-range (FR) system. All the hens had trimmed beaks and were genotypically brown. The information collected included feather cover, skin damage, beak condition, farm and poultry house characteristics, livestock performance and management.4. The prevalence of SFP in FC flocks was estimated at 32.9% (IC = 95%, [22.5; 43.3]) and the prevalence of cannibalism as 2.5% (IC = 95%, [0.7; 8.8]) at 70 weeks of age. The prevalence of SFP in FR flocks was estimated to be 23.8% (IC = 95%, [14.5; 31.1]) and the prevalence of cannibalism was 8.8% (IC = 95%, [4.3; 17.0]) at 61 weeks of age.5. In FC flocks, SFP was associated with the combination of genotype, type and length of perches, cage area per hen, type of lighting, number of hens per cage and farm location. In FR flocks, feather cover was associated with use of the outdoor run, lighting programme, genotype, farm location and date of house construction.

Association between Salivary Hypofunction and Food Consumption in the Elderlies. A Systematic Literature Review.

OBJECTIVES: This systematic literature review aims to summarize the existing scientific evidence about the association between a reduced salivary function and food consumption in elderly people. METHODS: A validated search strategy in two databases (PubMed and ISI Web of Knowledge) was carried out and retrieved papers together with their reference lists were screened by two independent reviewers. The quality of the included studies was critically appraised via the Quality Assessment Criteria for Evaluating Primary Research Papers. RESULTS: From the originally identified studies (n=391), only 15 articles (all cross-sectional studies) met the pre-fixed inclusion/exclusion criteria. The methodological quality of the included studies was in general good, although only 3 from 15 obtained the maximum score. The control of confounding factors was the quality variable more poorly rated in the selected studies. Salivary hypofunction was associated with a decrease of the objective chewing and swallowing abilities and taste perception. Moreover, most of the selected studies showed a relationship between salivary hypofunction and food consumption (in terms of appetite loss, unbalanced dietary intake and malnutrition), although no causality could be established. CONCLUSIONS: This study highlights the fact that salivary hypofunction definition and measurements are different across the studies. Therefore, future research efforts should focus on establishing a gold standard to define and identify salivary hypofunction throughout life and on performing longitudinal studies controlling for confounding factors to establish causality.

Perspectives on the amorphisation/milling relationship in pharmaceutical materials.

This paper presents an overview of recent advances in understanding the role of the amorphous state in the physical and chemical transformations of pharmaceutical materials induced by mechanical milling. The following points are addressed: (1) Is milling really able to amorphise crystals?, (2) Conditions for obtaining an amorphisation, (3) Milling of hydrates, (4) Producing amorphous state without changing the chemical nature, (5) Milling induced crystal to crystal transformations: mediation by an amorphous state, (6) Nature of the amorphous state obtained by milling, (7) Milling of amorphous compounds: accelerated aging or rejuvenation, (8) Specific recrystallisation behaviour, and (9) Toward a rationalisation and conceptual framework.

Dynamic nuclear polarization of a glassy matrix prepared by solid state mechanochemical amorphization of crystalline substances.

A mechanochemical "solvent-free" route is presented for the preparation of solid samples ready to be employed in the Dynamic Nuclear Polarization (DNP). (1)H-DNP build-up curves at 3.46 T as a function of temperature and radical concentration show steady state nuclear polarization of 10% (0.5% TEMPO concentration at 1.75 K).

Accelerated ketoprofen release from polymeric matrices: importance of the homogeneity/heterogeneity of excipient distribution.

Polymeric matrices loaded with 10-50% ketoprofen were prepared by hot-melt extrusion or spray-drying. Eudragit E, PVP, PVPVA and HPMC were studied as matrix formers. Binary "drug-Eudragit E" as well as ternary "drug-Eudragit E-PVP", "drug-Eudragit E-PVPVA" and "drug-Eudragit E-HPMC" combinations were investigated and characterized by optical macro/microscopy, SEM, particle size measurements, mDSC, X-ray diffraction and in vitro drug release studies in 0.1 M HCl. In all cases ketoprofen release was much faster compared to a commercially available product and the dissolution of the drug powder (as received). Super-saturated solutions were obtained, which were stable during at least 2 h. Importantly, not only the composition of the systems, but also their inner structure potentially significantly affected the resulting ketoprofen release kinetics: For instance, spray-drying ternary ketoprofen:Eudragit E:HPMC combinations led to a more homogenous HPMC distribution within the systems than hot-melt extrusion, as revealed by mDSC and X-ray diffraction. This more homogenous HPMC distribution resulted in more pronounced hindrance for water and drug diffusion and, thus, slower drug release from spray-dried powder compared to hot-melt extrudates of identical composition. This "homogeneity/heterogeneity effect" even overcompensated the "system size effect": the surface exposed to the release medium was much larger in the case of the spray-dried powder. All formulations were stable during storage at ambient conditions in open vials.

PLGAs bearing carboxylated side chains: novel matrix formers with improved properties for controlled drug delivery.

Novel PLGA derivatives bearing carboxylated side chains have been synthesized and used to encapsulate the fragile drug apomorphine HCl with a solid-in-oil-in-water solvent extraction/evaporation method. Blends of d,l-lactide and l-3-(2-Benzyloxycarbonyl)Ethyl-1,4-Dioxane-2,5-dione (BED) were co-polymerized at different ratios via ring-opening using benzyl alcohol as initiator. Optionally, the ester groups in the side chains as well as the terminal ester groups were hydrogenolyzed (leading to free COOH groups). For reasons of comparison, different types of "conventional" PLGAs were also synthesized and used for apomorphine HCl encapsulation. The polymers and microparticles were thoroughly characterized using SEC, (1)H NMR, DSC, SEM, X-ray and laser diffraction, Headspace-GC as well as in vitro drug release measurements in flow-through cells and agitated flasks. Importantly, microparticles based on the new polymers bearing carboxylic groups in the polymeric side chains: (i) allowed a significant reduction of the amount of residual solvent (dichloromethane), and (ii) provided different types of drug release patterns compared to microparticles based on "conventional" PLGAs (at least partially due to altered polymer degradation kinetics). Thus, they offer an interesting potential as novel matrix formers in controlled drug delivery systems, overcoming potential shortcomings of standard PLGAs.

Mechanism of solid state amorphization of glucose upon milling.

Crystalline α-glucose is known to amorphize upon milling at -15 °C while it remains structurally invariant upon milling at room temperature. We have taken advantage of this behavior to compare the microstructural evolutions of the material in both conditions in order to identify the essential microstructural features which drive the amorphization process upon milling. The investigations have been performed by differential scanning calorimetry and by powder X-ray diffraction. The results indicate that two different amorphization mechanisms occur upon milling: an amorphization at the surface of crystallites due to the mechanical shocks and a spontaneous amorphization of the crystallites as they reach a critical size, which is close to 200 Å in the particular case of α-glucose.

Calcite as a bone substitute. Comparison with hydroxyapatite and tricalcium phosphate with regard to the osteoblastic activity.

Close to the bone mineral phase, the calcic bioceramics, such as hydroxyapatite (HA) and ß-tricalcium phosphate (ß-TCP), are commonly used as substitutes or filling materials in bone surgery. Besides, calcium carbonate (CaCO3) is also used for their excellent biocompatibility and bioactivity. However, the problem with the animal-origin aragonite demands the new technique to synthesize pure calcite capable of forming 3D bone implant. This study aims to manufacture and evaluate a highly-pure synthetic crystalline calcite with good cytocompatibility regarding to the osteoblasts, comparing to that of HA and ß-TCP. After the manufacture of macroporous bioceramic scaffolds with the identical internal architecture, their cytocompatibility is studied through MC3T3-E1 osteoblasts with the tests of cell viability, proliferation, vitality, etc. The results confirmed that the studied process is able to form a macroporous material with a controlled internal architecture, and this synthesized calcite is non-cytotoxic and facilitate the cell proliferation. Indeed requiring further improvement, the studied calcite is definitely an interesting alternative not only to coralline aragonite but also to calcium phosphate ceramics, particularly in bone sites with the large bone remodelling.

Impact of the experimental conditions on drug release from parenteral depot systems: From negligible to significant.

The aim of this study was to evaluate the impact of the experimental conditions on drug release measurements from parenteral depot systems. Frequently applied setups were used, including agitated and "non-agitated" flasks and tubes, flow-though cells as well as agarose gels. The bulk fluid volumes and flow rates were varied. Lipid implants (prepared by direct compression or melting & casting) as well as PLGA-based microparticles (prepared by O/W or W/O/W or S/O/W solvent extraction/evaporation methods) were studied. Theophylline, lidocaine, prilocaine, propranolol HCl, dexamethasone and ibuprofen were used as model drugs at different initial loadings. In all cases, the release medium was phosphate buffer pH 7.4, kept constant at 37°C. Particle size analysis, SEM, X-ray diffraction, DSC analysis and mathematical modeling were applied to better understand the observed phenomena. Interestingly, the importance of the impact of the experimental conditions ranged from negligible to significant, depending on the specific type of drug delivery system and setup. Both, lipid implants as well as PLGA-based microparticles can exhibit more or less sensitive/robust drug release patterns. The observed differences in sensitivity could partially be explained in a mechanistic way, but in many cases they are not yet fully understood. A thorough understanding of the underlying drug release mechanisms can be very helpful. If the devices are poorly characterized and treated as "black boxes", great care must be taken when drawing conclusions from in vitro drug release measurements.

Controlled release implants based on cast lipid blends.

The aim of this study was to use lipid:lipid blends as matrix formers in controlled release implants. The systems were prepared by melting and casting and thoroughly characterized before and after exposure to the release medium. Based on the experimental results, a mechanistic realistic mathematical model was used to get further insight into the underlying drug release mechanisms. Importantly, broad spectra of drug release patterns could be obtained by simply varying the lipid:lipid blend ratio in implants based on Precirol ATO 5 (glyceryl palmitostearate):Dynasan 120 (hardened soybean oil) mixtures loaded with propranolol hydrochloride. Release periods ranging from a few days up to several months could be provided. Interestingly, the drug release rate monotonically decreased with increasing Dynasan 120 content, except for implants containing about 20-25% Precirol, which exhibited surprisingly high release rates. This could be attributed to the incomplete miscibility of the two lipids at these blend ratios: DSC thermograms showed phase separation in these systems. This is likely to cause differences in the implants' microstructure, which determines the mobility of water and dissolved drug as well as the mechanical stability of the systems. Purely diffusion controlled drug release was only observed at Precirol ATO 5 contents around 5-10%. In all other cases, limited drug solubility effects or matrix former erosion are also expected to play a major role. Thus, lipid:lipid blends are very interesting matrix formers in controlled release implants. However, care must be taken with respect to the mutual miscibility of the compounds: in case of phase separation, surprisingly high drug release rates might be observed.

Drug release mechanisms of cast lipid implants.

The aim of this work was to better understand which physicochemical processes are involved in the control of drug release from lipid implants prepared by melting and casting. Lipid implants gain steadily in importance as controlled parenteral drug delivery systems: In contrast to PLGA-based devices, no acidic microclimates are created, which can inactivate incorporated drugs. The melting and casting method offers various advantages over the commonly used direct compression technique. For example, powder de-mixing during manufacturing and highly challenging scale-up due to poor powder flowability are avoided. Importantly, broad spectra of drug release patterns can be easily provided by varying the type of lipid. The resulting drug release rates are generally lower than those of implants prepared by direct compression. This is probably due to the differences in the microstructure of the pore network of the systems. Drug or water diffusion plays a dominant role for the control of drug release, potentially combined with limited drug solubility effects, caused by the low amounts of water available within the implants. In the case of pure diffusion control, a mechanistic realistic mathematical theory is proposed, which allows for quantitative predictions of the effects of formulation parameters on the resulting drug release kinetics. Importantly, these theoretical predictions could be successfully confirmed by independent experiments. Thus, the obtained new insight into the underlying drug release mechanisms can significantly facilitate the optimization of this type of advanced drug delivery systems. This is particularly helpful if long release periods are targeted, requiring time-consuming experimental studies.

Solid state mutarotation of glucose.

It has been recently shown that mechanical milling can amorphize D-glucose without any mutarotation, giving rise to an anomerically pure amorphous sample. We have taken advantage of this exceptional possibility to study the kinetic of mutarotation in the amorphous solid state. The investigations have been performed in situ by time-resolved Raman spectroscopy. The results reveal an unexpected coupling between the mutarotation process and the structural relaxations involved in the glassy state.

Amorphization of sugar hydrates upon milling.

The possibility to amorphize anhydrous crystalline sugars, like lactose, trehalose and glucose, by mechanical milling was previously reported. We test here the possibility to amorphize the corresponding crystalline hydrates: lactose monohydrate, trehalose dihydrate and glucose monohydrate using fully identical milling procedures. The results show that only the first hydrate amorphizes while the other two remain structurally invariant. These different behaviours are attributed to the plasticizing effect of the structural water molecules which can decrease the glass transition temperature below the milling temperature. The results reveal clearly the fundamental role of the glass transition in the solid-state amorphization process induced by milling, and they also explain why crystalline hydrates are systematically more difficult to amorphize by milling than their anhydrous counterpart. The investigations have been performed by differential scanning calorimetry and powder X-ray diffraction.

First obtaining of glass solutions and phase diagram of glucose with fully tunable anomeric concentration.

In this article we show the possibility to form amorphous alpha-glucose/beta-glucose molecular alloys directly in the solid state by comilling crystalline alpha-glucose and crystalline beta-glucose. Contrary to the usual melt quenching process, milling does not induce any mutarotation so that alloys can be obtained for the whole range of anomeric concentration. This offers the unique possibility to explore the phase diagram of this binary system which appears to be a eutectic mixture. The structural and thermodynamic investigations have been performed by powder X-ray diffraction and differential scanning calorimetry.

Drug release from PLGA-based microparticles: effects of the "microparticle:bulk fluid" ratio.

The aim of this study was to better understand the importance of the "microparticle mass:bulk fluid volume" ratio during in vitro drug release measurements from PLGA microparticles. Initially porous/non-porous, ibuprofen/lidocaine/propranolol HCl-loaded systems were exposed to phosphate buffer pH 7.4 in agitated test tubes, varying the microparticle concentration from 5:1 to 20:1mg:mL. Interestingly, drug release was virtually unaffected by the "microparticle mass:bulk fluid volume" ratio in the case of initially porous, ibuprofen-loaded microparticles, exhibiting complete drug release within about 1 week. Optical microscopy, SEM, DSC and pH measurements of the bulk fluid revealed no major impact of the microparticle concentration on the systems' properties within the first couple of days. However, a more rapid and pronounced decrease in the pH of the release medium occurred after 10-14 d at elevated "microparticle mass:bulk fluid volume" ratios. This resulted in an accelerated: (i) decrease in the glass transition temperature, (ii) microparticle agglomeration, and (iii) increase in the internal and external microparticle porosity. Importantly, this phenomenon did not significantly affect drug release from initially porous, lidocaine-loaded microparticles, exhibiting complete release within about 18 d. In contrast, drug release became significantly faster at higher "microparticle mass:bulk fluid volume" ratios in the case of initially non-porous, lidocaine-loaded microparticles and initially porous, propranolol HCl-loaded systems, exhibiting complete release after 1 and 2 months, respectively. Thus, depending on the type of system, the "microparticle mass:bulk fluid volume" ratio may or may not affect the observed release kinetics in vitro. This should be carefully taken into account when defining the experimental conditions for drug release measurements from this type of advanced drug delivery systems.

Mixing effects in glass-forming Lennard-Jones mixtures.

Mixing effects have been investigated from molecular dynamics simulations at constant number of particles, volume, and temperature on the Kob-Andersen glass-forming Lennard-Jones atomic mixture A(x)B(1-x) for 0 < or = x < or = 1 compositions. Upon cooling, crystallization is observed for x < or = 0.5 and x > or = 0.9 compositions. The crystalline states can be described by a quite complex coexistence of voids (x < or = 0.5), point defects, and one or two crystal structures which were characterized and found identical to those reported by Fernandez and Harrowell [Phys. Rev. E 67, 011403 (2003)] from energy minimization. Amorphization is also seen at 0.6 < or = x < or = 0.8 compositions and it is suggested that both crystal structures, CsCl and fcc-hcp, do not compete at these compositions since only one type of crystalline seed is found in the liquid, either fcc/hcp or CsCl. A significant decrease in the diffusion constants for both A and B particles is also seen above x(A) approximately = 0.5. The problem of the extraordinary stability of the model against crystallization is discussed.

Phalloplasty in complete aphallia: pedicled anterolateral thigh flap.

A phalloplasty using the pedicled anterolateral thigh flap in three patients with aphallia is described. The technique, its advantages and disadvantages are discussed.

Low-frequency vibrational properties of lysozyme in sugar aqueous solutions: a Raman scattering and molecular dynamics simulation study.

The low-frequency (omega<400 cm(-1)) vibrational properties of lysozyme in aqueous solutions of three well-known protecting sugars, namely, trehalose, maltose, and sucrose, have been investigated by means of complementary Raman scattering experiments and molecular dynamics simulations. The comparison of the Raman susceptibility chi(")(omega) of lysozyme/water and lysozyme/sugar/water solutions at a concentration of 40 wt % with the chi(") of dry lysozyme suggests that the protein dynamics mostly appears in the broad peak around 60-80 cm(-1) that reflects the vibrations experienced by atoms within the cage formed by their neighbors, whereas the broad shoulder around 170 cm(-1) mainly stems from the intermolecular O-H...O stretching vibrations of water. The addition of sugars essentially induces a significant high frequency shift and intensity reduction of this band that reveal a slowing down of water dynamics and a distortion of the tetrahedral hydrogen bond network of water, respectively. Furthermore, the lysozyme vibrational densities of states (VDOS) have been determined from simulations of lysozyme in 37-60 wt % disaccharide aqueous solutions. They exhibit an additional broad peak around 290 cm(-1), in line with the VDOS of globular proteins obtained in neutron scattering experiments. The influence of sugars on the computed VDOS mostly appears on the first peak as a slight high-frequency shift and intensity reduction in the low-frequency range (omega<50 cm(-1)), which increase with the sugar concentration and with the exposition of protein residues to the solvent. These results suggest that sugars stiffen the environment experienced by lysozyme atoms, thereby counteracting the softening of protein vibrational modes upon denaturation, observed at high temperature in the Raman susceptibility of the lysozyme/water solution and in the computed VDOS of unfolded lysozyme in water. Finally, the Raman susceptibility of sugar/water solutions and the calculated VDOS of water in the different lysozyme solutions confirm that sugars induce a significant strengthening of the hydrogen bond network of water that may stabilize proteins at high temperatures.