The influence of formulation and manufacturing process parameters on the characteristics of lyophilized orally disintegrating tablets

Gelatin is a principal excipient used as a binder in the formulation of lyophilized orally disintegrating tablets. The current study focuses on exploiting the physicochemical properties of gelatin by varying formulation parameters to determine their influence on orally disintegrating tablet (ODT) characteristics. Process parameters, namely pH and ionic strength of the formulations, and ball milling were investigated to observe their effects on excipient characteristics and tablet formation. The properties and characteristics of the formulations and tablets which were investigated included: glass transition temperature, wettability, porosity, mechanical properties, disintegration time, morphology of the internal structure of the freeze-dried tablets, and drug dissolution. The results from the pH study revealed that adjusting the pH of the formulation away from the isoelectric point of gelatin, resulted in an improvement in tablet disintegration time possibly due to increase in gelatin swelling resulting in greater tablet porosity. The results from the ionic strength study revealed that the inclusion of sodium chloride influenced tablet porosity, tablet morphology and the glass transition temperature of the formulations. Data from the milling study showed that milling the excipients influenced formulation characteristics, namely wettability and powder porosity. The study concludes that alterations of simple parameters such as pH and salt concentration have a significant influence on formulation of ODT. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

Self-sustained clusters and ergodicity breaking in spin models

Self-sustained spin clusters are analytically linked to ergodicity breaking in fully connected Ising and Sherrington-Kirkpatick (SK) models, relating the less understood spin space to the well understood state space. This correspondence is established through the absence of clusters in the paramagnetic phase, the presence of one dominant cluster in the Ising ferromagnet, and the formation of nontrivial clusters in SK spin glass. Yet unobserved phenomena are also revealed such as a first order phase transition in cluster sizes in the SK ferromagnet. The method could be adapted to investigate other spin models. © 2013 American Physical Society.

Magneto-vibratory separation of glass and bronze granular mixtures immersed in a paramagnetic liquid

A fluid-immersed granular mixture may spontaneously separate when subjected to vertical vibration, separation occurring when the ratio of particle inertia to fluid drag is sufficiently different between the component species of the mixture. Here, we describe how fluid-driven separation is influenced by magneto-Archimedes buoyancy, the additional buoyancy force experienced by a body immersed in a paramagnetic fluid when a strong inhomogeneous magnetic field is applied. In our experiments glass and bronze mixtures immersed in paramagnetic aqueous solutions of MnCl2 have been subjected to sinusoidal vertical vibration. In the absence of a magnetic field the separation is similar to that observed when the interstitial fluid is water. However, at modest applied magnetic fields, magneto-Archimedes buoyancy may balance the inertia/fluid-drag separation mechanism, or it may dominate the separation process. We identify the vibratory and magnetic conditions for four granular configurations, each having distinctive granular convection. Abrupt transitions between these states occur at well-defined values of the magnetic and vibrational parameters. In order to gain insight into the dynamics of the separation process we use computer simulations based on solutions of the Navier-Stokes' equations. The simulations reproduce the experimental results revealing the important role of convection and gap formation in the stability of the different states.

Vitamin E-stabilised UHMWPE for orthopaedic implants:quantitative determination of vitamin E and characterisation of its transformation products

The fate of vitamin E and the formation and identification of its transformation products were investigated at different stages of the manufacturing process of commercially produced cross-linked (by γ-irradiation) UHMWPE stabilised with vitamin E (vitamin E infused-post irradiation) used for tibia-components (as articulating surfaces) in total knee arthroplasty (total knee replacement). Vitamin E (α-tocopherol) and its transformation products were extracted from microtomed Tibia films and the different products were separated, isolated, purified using high performance liquid chromatography (HPLC), and characterised by spectroscopic methods and LC-MS. The amount of vitamin E and that of the products formed in the different Tibia samples and in their extracts were also quantified using FTIR and HPLC analysis and calibration curves. Thorough analysis of the Tibia extracts has shown that a number of vitamin E transformation products were formed at different concentrations at two selected stages of the implant manufacturing process that is before and after sterilisation by γ-irradiation. The identified products were found to correspond mainly to different stereoisomeric forms of a small number of vitamin E transformation products. Most of the observed products were of dimeric and trimeric nature with their identity confirmed through a detailed study of their spectral and chromatographic characteristics. It was found that the products of vitamin E, prior to the sterilisation step but after the crosslinking and doping of vitamin E, were mainly the dihydroxydimers and trimers (Tibia samples at this stage are referred to as “Tibia-VEPE”). After sterilisation and completion of the manufacturing process, additional dimers of vitamin E were also formed (Tibia samples at this stage are referred to as ‘Tibia-VEPE-Sterile’), Furthermore, two tocopherol-derived aldehydes (aldehyde 5-formyl-γ-tocopherol and aldehyde 7-formyl-γ-tocopherol) were also formed but at very low concentrations especially in the Tibia-VEPE-Sterile samples. The question of whether vitamin E becomes chemically reacted (grafted) onto the polymer matrix during the manufacturing process of the Tibia is also addressed.

VEGF-E activates endothelial nitric oxide synthase to induce angiogenesis via cGMP and PKG-independent pathways

Vascular endothelial growth factor-A (VEGF), which binds to both VEGF receptor-1 (Flt1) and VEGFR-2 (KDR/Flk-1), requires nitric oxide (NO) to induce angiogenesis in a cGMP-dependent manner. Here we show that VEGF-E, a VEGFR-2-selective ligand stimulates NO release and tube formation in human umbilical vein endothelial cells (HUVEC). Inhibition of phospholipase Cgamma (PLCgamma) with U73122 abrogated VEGF-E induced endothelial cell migration, tube formation and NO release. Inhibition of endothelial nitric oxide synthase (eNOS) using l-NNA blocked VEGF-E-induced NO release and angiogenesis. Pre-incubation of HUVEC with the soluble guanylate cyclase inhibitor, ODQ, or the protein kinase G (PKG) inhibitor, KT-5823, had no effect on angiogenesis suggesting that the action of VEGF-E is cGMP-independent. Our data provide the first demonstration that VEGFR-2-mediated NO signaling and subsequent angiogenesis is through a mechanism that is dependent on PLCgamma but independent of cGMP and PKG.

Public R&D policies and private R&D investment:a survey of the empirical evidence

The importance of R&D investment in explaining economic growth is well documented in the literature. Policies by modern governments increasingly recognise the benefits of supporting R&D investment. Government funding has, however, become an increasingly scarce resource in times of financial crisis and economic austerity. Hence, it is important that available funds are used and targeted effectively. This paper offers the first systematic review and critical discussion of what the R&D literature has to say currently about the effectiveness of major public R&D policies in increasing private R&D investment. Public policies are considered within three categories, R&D tax credits and direct subsidies, support of the university research system and the formation of high-skilled human capital, and support of formal R&D cooperations across a variety of institutions. Crucially, the large body of more recent literature observes a shift away from the earlier findings that public subsidies often crowd-out private R&D to finding that subsidies typically stimulate private R&D. Tax credits are also much more unanimously than previously found to have positive effects. University research, high-skilled human capital, and R&D cooperation also typically increase private R&D. Recent work indicates that accounting for non-linearities is one area of research that may refine existing results. © 2014 John Wiley & Sons Ltd.

The MK2/3 cascade regulates AMPAR trafficking and cognitive flexibility

The interplay between long-term potentiation and long-term depression (LTD) is thought to be involved in learning and memory formation. One form of LTD expressed in the hippocampus is initiated by the activation of the group 1 metabotropic glutamate receptors (mGluRs). Importantly, mGluRs have been shown to be critical for acquisition of new memories and for reversal learning, processes that are thought to be crucial for cognitive flexibility. Here we provide evidence that MAPK-activated protein kinases 2 and 3 (MK2/3) regulate neuronal spine morphology, synaptic transmission and plasticity. Furthermore, mGluR-LTD is impaired in the hippocampus of MK2/3 double knockout (DKO) mice, an observation that is mirrored by deficits in endocytosis of GluA1 subunits. Consistent with compromised mGluR-LTD, MK2/3 DKO mice have distinctive deficits in hippocampal-dependent spatial reversal learning. These novel findings demonstrate that the MK2/3 cascade plays a strategic role in controlling synaptic plasticity and cognition. © 2014 Macmillan Publishers Limited. All rights reserved.

Development of potent and selective tissue transglutaminase inhibitors:their effect on TG2 function and application in pathological conditions

Potent-selective peptidomimetic inhibitors of tissue transglutaminase (TG2) were developed through a combination of protein-ligand docking and molecular dynamic techniques. Derivatives of these inhibitors were made with the aim of specific TG2 targeting to the intra- and extracellular space. A cell-permeable fluorescently labeled derivative enabled detection of in situ cellular TG2 activity in human umbilical cord endothelial cells and TG2-transduced NIH3T3 cells, which could be enhanced by treatment of cells with ionomycin. Reaction of TG2 with this fluorescent inhibitor in NIH3T3 cells resulted in loss of binding of TG2 to cell surface syndecan-4 and inhibition of translocation of the enzyme into the extracellular matrix, with a parallel reduction in fibronectin deposition. In human umbilical cord endothelial cells, this same fluorescent inhibitor also demonstrated a reduction in fibronectin deposition, cell motility, and cord formation in Matrigel. Use of the same inhibitor in a mouse model of hypertensive nephrosclerosis showed over a 40% reduction in collagen deposition.

The spatial patterns of β-amyloid (Aβ) deposits and neurofibrillary tangles (NFT) in late-onset sporadic Alzheimer's disease

The spatial patterns of β-amyloid (Aβ) deposits and neurofibrillary tangles (NFT) were studied in areas of the cerebral cortex in 16 patients with the late-onset, sporadic form of Alzheimer's disease (AD). Diffuse, primitive, and classic Aβ deposits and NFT were aggregated into clusters; the clusters being regularly distributed parallel to the pia mater in many areas. In a significant proportion of regions, the sizes of the regularly distributed clusters approximated to those of the cells of origin of the cortico-cortical projections. The diffuse and primitive Aβ deposits exhibited a similar range of spatial patterns but the classic Aβ deposits occurred less frequently in large clusters >6400m. In addition, the NFT often occurred in larger regularly distributed clusters than the Aβ deposits. The location, size, and distribution of the clusters of Aβ deposits and NFT supports the hypothesis that AD is a 'disconnection syndrome' in which degeneration of specific cortico-cortical and cortico-hippocampal pathways results in synaptic disconnection and the formation of clusters of NFT and Aβ deposits. © 2011 Nova Science Publishers, Inc.

Silica promoted self-assembled mesoporous aluminas. Impact of the silica precursor on the structural, textural and acidic properties

This paper investigates the effect of silica addition on the structural, textural and acidic properties of an evaporation induced self-assembled (EISA) mesoporous alumina. Two silica addition protocols were applied while maintaining the EISA synthesis route. The first route is based on the addition of a Na-free colloidal silica suspension (Ludox®), and the second method consists of the co-hydrolysis of tetraethyl orthosilicate (TEOS) with aluminium tri-sec-butoxide, to favour a more intimate mixing of the Al- and Si-hydrolysed species. The properties of the so derived materials were compared to the SiO2-free counterpart. The SiO2 addition was always beneficial from a structural and textural standpoint. TEOS appears to have a truly promoting effect; the ordering, surface area and pore volume are all improved. For Ludox®, the enhancement comes from the formation of smaller pores by a densification of the structure. The crystallization of γ-alumina depends on the interaction between the Al- and Si-species in the mesophase. Ludox®-based materials achieved crystallization at 750 °C but the intimate mixing in the TEOS-based mesophases shows a suppression of the phase transformation by 50-100 °C, with respect to the SiO2-free counterpart. This reduces the textural features substantially. For all SiO2-modified materials, the enhancement in the surface area is not accompanied by a concomitant improvement of total acidity, and the formation of weak Lewis acid sites was promoted. These effects were ascribed to SiO2 migration to the surface that blocks part of the acidity.

One-dimensional optical wave turbulence:experiment and theory

We present a review of the latest developments in one-dimensional (1D) optical wave turbulence (OWT). Based on an original experimental setup that allows for the implementation of 1D OWT, we are able to show that an inverse cascade occurs through the spontaneous evolution of the nonlinear field up to the point when modulational instability leads to soliton formation. After solitons are formed, further interaction of the solitons among themselves and with incoherent waves leads to a final condensate state dominated by a single strong soliton. Motivated by the observations, we develop a theoretical description, showing that the inverse cascade develops through six-wave interaction, and that this is the basic mechanism of nonlinear wave coupling for 1D OWT. We describe theory, numerics and experimental observations while trying to incorporate all the different aspects into a consistent context. The experimental system is described by two coupled nonlinear equations, which we explore within two wave limits allowing for the expression of the evolution of the complex amplitude in a single dynamical equation. The long-wave limit corresponds to waves with wave numbers smaller than the electrical coherence length of the liquid crystal, and the opposite limit, when wave numbers are larger. We show that both of these systems are of a dual cascade type, analogous to two-dimensional (2D) turbulence, which can be described by wave turbulence (WT) theory, and conclude that the cascades are induced by a six-wave resonant interaction process. WT theory predicts several stationary solutions (non-equilibrium and thermodynamic) to both the long- and short-wave systems, and we investigate the necessary conditions required for their realization. Interestingly, the long-wave system is close to the integrable 1D nonlinear Schrödinger equation (NLSE) (which contains exact nonlinear soliton solutions), and as a result during the inverse cascade, nonlinearity of the system at low wave numbers becomes strong. Subsequently, due to the focusing nature of the nonlinearity, this leads to modulational instability (MI) of the condensate and the formation of solitons. Finally, with the aid of the probability density function (PDF) description of WT theory, we explain the coexistence and mutual interactions between solitons and the weakly nonlinear random wave background in the form of a wave turbulence life cycle (WTLC).

A distance education case study: A comparison of instructional delivery methods practiced by higher education faculty and emerging standards

The purpose of this research was to compare the delivery methods as practiced by higher education faculty teaching distance courses with recommended or emerging standard instructional delivery methods for distance education. Previous research shows that traditional-type instructional strategies have been used in distance education and that there has been no training to distance teach. Secondary data, however, appear to suggest emerging practices which could be pooled toward the development of standards. This is a qualitative study based on the constant comparative analysis approach of grounded theory.^ Participants (N = 5) of this study were full-time faculty teaching distance education courses. The observation method used was unobtrusive content analysis of videotaped instruction. Triangulation of data was accomplished through one-on-one in-depth interviews and from literature review. Due to the addition of non-media content being analyzed, a special time-sampling technique was designed by the researcher--influenced by content analyst theories of media-related data--to sample portions of the videotape instruction that were observed and counted. A standardized interview guide was used to collect data from in-depth interviews. Coding was done based on categories drawn from review of literature, and from Cranton and Weston's (1989) typology of instructional strategies. The data were observed, counted, tabulated, analyzed, and interpreted solely by the researcher. It should be noted however, that systematic and rigorous data collection and analysis led to credible data.^ The findings of this study supported the proposition that there are no standard instructional practices for distance teaching. Further, the findings revealed that of the emerging practices suggested by proponents and by faculty who teach distance education courses, few were practiced even minimally. A noted example was the use of lecture and questioning. Questioning, as a teaching tool was used a great deal, with students at the originating site but not with distance students. Lectures were given, but were mostly conducted in traditional fashion--long in duration and with no interactive component.^ It can be concluded from the findings that while there are no standard practices for instructional delivery for distance education, there appears to be sufficient information from secondary and empirical data to initiate some standard instructional practices. Therefore, grounded in this research data is the theory that the way to arrive at some instructional delivery standards for televised distance education is a pooling of the tacitly agreed-upon emerging practices by proponents and practicing instructors. Implicit in this theory is a need for experimental research so that these emerging practices can be tested, tried, and proven, ultimately resulting in formal standards for instructional delivery in television education. ^

The non-linear acousto-mechanical and thermodynamic response of spherical absorbers to laser pulses of various temporal profiles

This study is to theoretically investigate shockwave and microbubble formation due to laser absorption by microparticles and nanoparticles. The initial motivation for this research was to understand the underlying physical mechanisms responsible for laser damage to the retina, as well as the predict threshold levels for damage for laser pulses with of progressively shorter durations. The strongest absorbers in the retina are micron size melanosomes, and their absorption of laser light causes them to accrue very high energy density. I theoretically investigate how this absorbed energy is transferred to the surrounding medium. For a wide range of conditions I calculate shockwave generation and bubble growth as a function of the three parameters; fluence, pulse duration and pulse shape. In order to develop a rigorous physical treatment, the governing equations for the behavior of an absorber and for the surrounding medium are derived. Shockwave theory is investigated and the conclusion is that a shock pressure explanation is likely to be the underlying physical cause of retinal damage at threshold fluences for sub-nanosecond pulses. The same effects are also expected for non-biological micro and nano absorbers. ^

Anti-quorum sensing agents from south Florida medicinal plants and their attenuation of Pseudomonas aeruginosa pathogenicity

With the difficulty in treating recalcitrant infections and the growing resistance to antibiotics, new therapeutic modalities are becoming increasingly necessary. The interruption of bacterial quorum sensing (QS), or cell-cell communication is known to attenuate virulence, while limiting selective pressure toward resistance. This study initiates an ethnobotanically-directed search for QS inhibiting agents in south Florida medicinal plants. Fifty plants were screened for anti-QS activity using two biomonitor strains, Chromobacterium violaceum and Agrobacterium tumefaciens. Of these plants, six showed QS inhibition: Conocarpus erectus L. (Combretaceae), Chamaecyce hypericifolia (L.) Millsp. (Euphorbiaceae), Callistemon viminalis (Sol.ex Gaertn.) G. Don (Myrtaceae), Bucida burceras L. (Combretaceae), Tetrazygia bicolor (Mill.) Cogn. (Melastomataceae), and Quercus virginiana Mill. (Fagaceae). These plants were further examined for their effects on the QS system and virulence of Pseudomonas aeruginosa, an intractable opportunistic pathogen responsible for morbidity and mortality in the immunocompromised patient. C. erectus, B. buceras, and C. viminalis were found to significantly inhibit multiple virulence factors and biofilm formation in this organism. Each plant presented a distinct profile of effect on QS genes and signaling molecules, suggesting varying modes of action. Virulence attenuation was observed with marginal reduction of bacterial growth, suggesting quorum quenching mechanisms unrelated to static or cidal effects. Extracts of these plants were also investigated for their effects on P. aeruginosa killing of the nematode Caenorhabditis elegans. Results were evaluated in both toxin-based and infection-based assays with P. aeruginosa strains PA01 and PA14. Overall nematode mortality was reduced 50-90%. There was no indication of host toxicity, suggesting the potential for further development as anti-infectives. Using low-pressure chromatography and HPLC, two stereoisomeric ellagitannins, vescalagin and castalagin were isolated from an aqueous extract of C. erectus . Structures were confirmed via mass spectrometry and NMR spectroscopy. Both ellagitannins were shown to decrease signal production, QS gene expression, and virulence factor production in P. aeruginosa. This study introduces a potentially new therapeutic direction for the treatment of bacterial infections. In addition, this is the first report of vescalagin and castalagin being isolated from C. erectus, and the first report of ellagitannin activity on the QS system.

Interactions between endothelin receptor B and transcription factors Sox10 and Pax3 in the melanocyte lineage

Genetic interactions that underlie developmental processes such as cell differentiation and pattern formation are complex and difficult to elucidate. Neural Crest (NC) cells and their derivatives offer an optimal system in which to probe for these complex interactions as they acquire different cell fates and constitute a variety of structures. The transcription factors Sox10 and Pax3 as well as the transmembrane receptor Endothelin receptor b (Ednrb) are temporally and spatially co-expressed early in NC cells and mutations in these genes lead to similar hypopigmentation phenotypes due to a reduced number of NC-derived melanocyte precursors, the melanoblasts. The goal of this study was to establish whether Sox10 and Ednrb or Pax3 and Ednrb interact to promote normal murine melanocyte development. Crosses of Sox10 or Pax3 with Ednrb heterozygous mutants showed that the double heterozygous hypopigmentation phenotype was significantly more pronounced than phenotypes of single heterozygotes, implying that a synergistic interaction exists between Sox10 and Ednrb and Pax3 and Ednrb. This interaction was further explored by the attempt to rescue the Sox10 and Pax3 hypopigmentation phenotypes by the transgenic addition of Ednrb to melanoblasts. Pigmentation was completely restored in the Sox10 and partially restored in the Pax3 mutant mice. The comparison of the number of melanoblasts in transgenic and non-transgenic Sox10 mutant embryos showed that the transgenic rescue occurred as early as E11.5, a critical time for melanoblast population expansion. Cell survival assays indicated that the rescue was not due to an effect of the transgene on melanoblast survival. A novel phenotype arose when studying the interaction between Ednrb and Pax3. Newborns appeared normal but by 3.5 weeks of age, the affected pups were smaller than normal littermates and developed a dome-shaped head; some also developed thoracic kyphosis. Affected pups were dead by 4 weeks of age: 80% were Pax3Sp/+ and 75% were female. When compared to normal littermates, affected mice had brains with enlarged 4th ventricles and more glia while skeletal staining showed kyphosis, wider rib cages and pelvic differences. An epistatic interaction resulting from the mixing of genetic backgrounds that is exacerbated in the presence of Pax3 heterozygosity is suspected.