Cooperative Jahn–Teller effect and the role of strain in the tetragonal-to-cubic phase transition in MgxCu1

Temperature and composition dependences of the I41/amd → [Fd\bar 3m] phase transition in the MgxCu1 − xCr2O4 spinel solid solution, due to the melting of the cooperative Jahn–Teller distortion, have been studied by means of single-crystal X-ray diffraction. Crystals with x = 0, 0.10, 0.18, 0.43, 0.46, 0.53, 1 were grown by flux decomposition methods. All crystals have been refined in the tetragonal I41/amd space group except for the Mg end-member, which has cubic symmetry. In MgxCu1 − xCr2O4 the progressive substitution of the Jahn–Teller, d9 Cu2+ cation with spherical and closed-shell Mg2+ has a substantial effect on the crystal structure, such that there is a gradual reduction of the splitting of a and c unit-cell parameters and flattening of the tetrahedra. Single-crystal diffraction data collected in situ up to T = 1173 K show that the tetragonal-to-cubic transition temperature decreases with increasing Mg content. The strength of the Cu—Cu interaction is, in effect, modulated by varying the Cu/Mg ratio. Structure refinements of diffraction data collected at different temperatures reveal that heating results in a gradual reduction in the tetrahedron compression, which remains significant until near the transition temperature, however, at which point the distortion of the tetrahedra rapidly vanishes. The spontaneous strain arising in the tetragonal phase is large, amounting to 10% shear strain, et, and ∼ 1% volume strain, Vs, in the copper chromite end-member at room temperature. Observed strain relationships are consistent with pseudoproper ferroelastic behaviour ([e_{\rm t}^2] ∝ Vs ∝ [q_{\rm JT}^2], where qJT is the order parameter). The I41/amd → [Fd\bar 3m] phase transition is first order in character for Cu-rich samples and then evolves towards second-order character. Although a third order term is permitted by symmetry in the Landau expansion, this behaviour appears to be more accurately represented by a 246 expansion with a change from negative to positive values of the fourth-order coefficient with progressive dilution of the Jahn–Teller cation

A dynamic role of mastermind-like 1. A journey through the main (path)ways between development and cancer

Major signaling pathways, such as Notch, Hedgehog (Hh), Wnt/β-catenin and Hippo, are targeted by a plethora of physiological and pathological stimuli, ultimately resulting in the modulation of genes that act coordinately to establish specific biological processes. Many biological programs are strictly controlled by the assembly of multiprotein complexes into the nucleus, where a regulated recruitment of specific transcription factors and coactivators on gene promoter region leads to different transcriptional outcomes. MAML1 results to be a versatile coactivator, able to set up synergistic interlinking with pivotal signaling cascades and able to coordinate the network of cross-talking pathways. Accordingly, despite its original identification as a component of the Notch signaling pathway, several recent reports suggest a more articulated role for MAML1 protein, showing that it is able to sustain/empower Wnt/β-catenin, Hh and Hippo pathways, in a Notch-independent manner. For this reason, MAML1 may be associated to a molecular “switch”, with the function to control the activation of major signaling pathways, triggering in this way critical biological processes during embryonic and post-natal life. In this review, we summarize the current knowledge about the pleiotropic role played by MAML proteins, in particular MAML1, and we recapitulate how it takes part actively in physiological and pathological signaling networks. On this point, we also discuss the contribution of MAML proteins to malignant transformation. Accordingly, genetic alterations or impaired expression of MAML proteins may lead to a deregulated crosstalk among the pathways, culminating in a series of pathological disorders, including cancer development. Given their central role, a better knowledge of the molecular mechanisms that regulate the interplay of MAML proteins with several signaling pathways involved in tumorigenesis may open up novel opportunities for an attractive molecular targeted anticancer therapy

Erodible drug delivery systems for time-controlled release into the gastrointestinal tract

In oral delivery, lag phases of programmable duration that precede drug release may be advantageous in a number of instances, e.g. to meet chronotherapeutic needs or pursue colonic delivery. Systems that give rise to characteristic lag phases in their release profiles, i.e. intended for time-controlled release, are generally composed of a drug-containing core and a functional polymeric barrier. According to the nature of the polymer, the latter may delay the onset of drug release by acting as a rupturable, permeable or erodible boundary layer. Erodible systems are mostly based on water swellable polymers, such as hydrophilic cellulose ethers, and the release of the incorporated drug is deferred through the progressive hydration and erosion of the polymeric barrier upon contact with aqueous fluids. The extent of delay depends on the employed polymer, particularly on its viscosity grade, and on the thickness of the layer applied. The manufacturing technique may also have an impact on the performance of such systems. Double-compression and spray-coating have mainly been used, resulting in differing technical issues and release outcomes. In this article, an update on delivery systems based on erodible polymer barriers (coatings, shells) for time-controlled release is presented

Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics

A decrease in the release rate over time is typically encountered when dealing with hydrophilic matrix systems for oral prolonged release due to progressive increase of the distance the drug molecules have to cover to diffuse outwards and reduction of the area of the glassy matrix at the swelling front. In order to solve this issue, a novel formulation approach based on non-uniform distribution of the active ingredient throughout the swellable polymer matrix was proposed and evaluated. Various physical mixtures of polymer (high-viscosity hypromellose) and drug tracer (acetaminophen), having decreasing concentrations of the latter, were applied by powder-layering onto inert core seeds. The resulting gradient matrices showed to possess satisfactory physico-technological characteristics, with spherical shape and consistent thickness of the layers sequentially applied. The non-uniform matrix composition pursued was confirmed by Raman mapping analysis. As compared with a system having uniform distribution of the drug tracer, the multi-layer formulations were proved to enhance linearity of release. The simple design concept, advantageous technique, which involves no solvents nor high-impact drying operations, and the polymeric material of established use make the delivery platform hereby proposed a valuable strategy to improve the performance of hydrophilic matrix systems

Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility

A decrease in the drug release rate over time typically affects the performance of hydrophilic matrices for oral prolonged release. To address such an issue, a Non-Uniform Drug Distribution Matrix (NUDDMat) based on hypromellose was proposed and demonstrated to yield zero-order release. The system consisted of 5 overlaid layers, applied by powder layering, having drug concentration decreasing from the inside towards the outside of the matrix according to a descending staircase function. In the present study, manufacturing and performance of the described delivery platform were evaluated using drug tracers having different water solubility. Lansoprazole, acetaminophen and losartan potassium were selected as slightly (SST), moderately (MST) and highly (HST) soluble tracers. By halving the thickness of the external layer, which contained no drug, linear release of HST and MST was obtained. The release behavior of the NUDDMat system loaded with a drug having pH-independent solubility was shown to be consistent in pH 1.2, 4.5 and 6.8 media. Based on these results, feasibility of the NUDDMat platform by powder layering was demonstrated using drugs having different physico-technological characteristics. Moreover, its ability to generate zero-order release was proved in the case of drugs with water solubility in a relatively wide range

Fatal systemic toxoplasmosis in a 3-month-old young tibetan goat (Capra hircus)

Background: Toxoplasmosis is one of the most common parasitic infections in both humans and animals. It is a frequent cause of abortion and stillbirth in intermediate hosts, especially sheep and goats but rarely causes fatal clinical form in adult animals. Case presentation: In contrast, the study reports an unusual fatal case of toxoplasmosis in a young goat naturally infected with type II strain of Toxoplasma gondii. A three-month-old female goat was presented with dyspnea and died few days later. Grossly, lungs were firm, edematous and mottled with disseminated whitish areas. Generalized lymphadenopathy was found. The histopathological examination showed necrotic interstitial bronchopneumonia and necrotizing lymphadenitis with intralesional free and clustered within macrophages tachyzoites of T. gondii. DNA extracted from lungs and lymph nodes was positive for T. gondii by a fast qPCR. PCR-RFLP analysis and sequencing of GRA6 gene showed that the isolated strains belonged to type II genotype. Conclusions: This is an unusual report of acute systemic toxoplasmosis caused by the type II strain of T. gondii with a fatal outcome in a young goat

In vitro and human pharmacoscintigraphic evaluation of an oral 5-ASA delivery system for colonic release

5-aminosalicylic acid (5-ASA) is the most widely used drug for the treatment of ulcerative colitis. The benefits of targeted delivery of 5-ASA to the large intestine are well known, resulting in reduced systemic absorption and increased local concentrations at the disease site. In the present study, a 5-ASA colon delivery system based on the time-dependent strategy, exploiting the relatively consistent small intestinal transit time (SITT), was manufactured and evaluated in vitro as well as in vivo. The system was obtained by successive spray-coating of an immediate-release tablet core with low-viscosity HPMC and Eudragit (R) L. The enteric film was effective in preventing release during the acidic stage of the in vitro test, while the HPMC coating brought about reproducible lag phases prior to release in phosphate buffer medium. A gamma-scintigraphy investigation pointed out that, following administration to fasted and fed volunteers, disintegration of the units never occurred prior to colon arrival. In all cases, a lag time preceded the appearance of the drug and its N-acetyl metabolite in the blood-stream, which was found to correlate with the time of disintegration in a linear mode. The plasma levels of the drug and metabolite as well as their cumulative urinary recovery were relatively low with respect to those reported when 5-ASA is delivered to the small bowel

Retentive device for intravesical drug delivery based on water-induced shape memory response of poly(vinyl alcohol): design concept and 4D printing feasibility

The use of shape memory polymers exhibiting water-induced shape recovery at body temperature and water solubility was proposed for the development of indwelling devices for intravesical drug delivery. These could be administered via catheter in a suitable temporary shape, retained in the bladder for a programmed period of time by recovery of the original shape and eliminated with urine following dissolution/erosion. Hot melt extrusion and fused deposition modeling 3D printing were employed as the manufacturing techniques, the latter resulting in 4D printing because of the shape modifications undergone by the printed item over time. Pharmaceutical-grade poly(vinyl alcohol) was selected based on its hot-processability, availability in different molecular weights and on preliminary data showing water-induced shape memory behavior. Specimens having various original and temporary geometries as well as compositions, successfully obtained, were characterized by differential scanning calorimetry and dynamic-mechanical thermal analysis as well as for fluid uptake, mass loss, shape recovery and release behavior. The samples exhibited the desired ability to recover the original shape, consistent in kinetics with the relevant thermo-mechanical properties, and concomitant prolonged release of a tracer. Although preliminary in scope, this study indicated the viability of the proposed approach to the design of retentive intravesical delivery systems

Dry coating of solid dosage forms : an overview of processes and applications

Dry coating techniques enable manufacturing of coated solid dosage forms with no, or very limited, use of solvents. As a result, major drawbacks associated with both organic solvents and aqueous coating systems can be overcome, such as toxicological, environmental, and safety-related issues on the one hand as well as costly drying phases and impaired product stability on the other. The considerable advantages related to solventless coating has been prompting a strong research interest in this field of pharmaceutics. In the article, processes and applications relevant to techniques intended for dry coating are analyzed and reviewed. Based on the physical state of the coat-forming agents, liquid- and solid-based techniques are distinguished. The former include hot-melt coating and coating by photocuring, while the latter encompass press coating and powder coating. Moreover, solventless techniques, such as injection molding and three-dimensional printing by fused deposition modeling, which are not purposely conceived for coating, are also discussed in that they would open new perspectives in the manufacturing of coated-like dosage forms