Mitochondrial disorders (MIDs) occasionally manifest as polyneuropathy either as the dominant feature or as one of many other manifestations (inherited mitochondrial neuropathy). MIDs in which polyneuropathy is the dominant feature, include NARP syndrome due to the transition m.8993T>, CMT2A due to MFN2 mutations, CMT2K and CMT4A due to GDAP1 mutations, and axonal/demyelinating neuropathy with external ophthalmoplegia due to POLG1 mutations. MIDs in which polyneuropathy is an inconstant feature among others is the MELAS syndrome, MERRF syndrome, LHON, Mendelian PEO, KSS, Leigh syndrome, MNGIE, SANDO; MIRAS, MEMSA, AHS, MDS (hepato-cerebral form), IOSCA, and ADOA syndrome. In the majority of the cases polyneuropathy presents in a multiplex neuropathy distribution. Nerve conduction studies may reveal either axonal or demyelinated or mixed types of neuropathies. If a hereditary neuropathy is due to mitochondrial dysfunction, the management of these patients is at variance from non-mitochondrial hereditary neuropathies. Patients with mitochondrial hereditary neuropathy need to be carefully investigated for clinical or subclinical involvement of other organs or systems. Supportive treatment with co-factors, antioxidants, alternative energy sources, or lactate lowering agents can be tried. Involvement of other organs may require specific treatment. Mitochondrial neuropathies should be included in the differential diagnosis of hereditary neuropathies.

Alternating multiblock copolymers composed of short blocks of poly(ethylene oxide) (PEO) and poly(epsilon-caprolactone) (PCL) or poly(L-lactic acid) (PLLA) were synthesized by a coupling reaction. The block copolymers of relatively high molecular weights (M(n)20,000) formed a physically crosslinked thermoplastic network, while low molecular weight polymers were water-soluble. The block copolymers demonstrated solubility in a variety of solvents including acetone, tetrahydrofuran, methylene chloride, dioxane, water/acetone mixtures, and water/ethanol mixtures. The degree of swelling, optical transparency, and mechanical property of the films, prepared by a solvent casting method, were affected by the nature of the hydrophobic block used, polymer composition, temperature, and thermal history. The crystalline melting temperatures of PCL and PLLA in the block copolymers were significantly lowered due to the chemical structure of difunctional PCL and PLLA, and partial phase mixing with PEO segments. The properties of the block copolymers may be useful for biomedical applications as well as controlled drug release formulations. When PEO/PLLA multiblock copolymers were applied as a wound healing material loaded with basic fibroblast growth factor (bFGF), the feasibility study showed improved wound healing when compared to controls of no treatment and the same wound covering without bFGF, indicating that a certain degree of the bioactivity of bFGF is preserved.

ABA-triblock copolyethers 1a-1c as linear polymeric binders, in combination with clay nanosheets (CNSs), afford high-water-content moldable supramolecular hydrogels with excellent mechanical properties by constructing a well-developed crosslinked network in water. The linear binders carry in their terminal A blocks guanidinium ion (Gu(+)) pendants for adhesion to the CNS surface, while their central B block comprises poly(ethylene oxide) (PEO) that serves as a flexible linker for adhered CNSs. Although previously reported dendritic binder 2 requires multistep synthesis and purification, the linear binders can be obtained in sizable quantities from readily available starting materials by controlled polymerization. Together with dendritic reference 2, the modular nature of compounds 1a-1c with different numbers of Gu(+) pendants and PEO linker lengths allowed for investigating how their structural parameters affect the gel network formation and hydrogel properties. The newly obtained hydrogels are mechanically as tough as that with 2, although the hydrogelation takes place more slowly. Irrespective of which binder is used, the supramolecular gel network has a shape memory feature upon drying followed by rewetting, and the gelling water can be freely replaced with ionic liquids and organic fluids, affording novel clay-reinforced iono- and organogels, respectively.

Pyrazine-labeled multicompartment nanostructures are shown to exhibit enhanced pH-responsive blue-shifted fluorescence emission intensities compared to their simpler core-shell spherical analogs. An amphiphilic linear triblock terpolymer of ethylene oxide, N-acryloxysuccinimide, and styrene, PEO(45)-b-PNAS(105)-b-PS(45), which lacks significant incompatibility for the hydrophobic block segments and undergoes gradual hydrolysis of the NAS units, underwent supramolecular assembly in mixtures of organic solvent and water to afford multicompartment micelles (MCMs) with a narrow size distribution. The assembly process was followed over time and found to evolve from individual polymer nanodroplets containing internally phase segregated domains, of increasing definition, and ultimately to dissociate into discrete micelles. Upon covalent cross-linking of the MCMs with pH-insensitive pyrazine-based diamino cross-linkers, pH-responsive, photonic multicompartment nanostructures (MCNs) were produced. These MCNs exhibited significant enhancement of overall structural stability, in comparison with the MCMs, and internal structural tunability through the cross-linking chemistry. Meanwhile, the complex compartmentalized morphology exerted unique pH-responsive fluorescence dual-emission properties, indicating promise in ratiometric pH-sensing applications.

Poly(ethylene oxide) (PEO) was tested as a polymer matrix for solid dispersion to enhance drug bioavailability. Solid state nuclear magnetic resonance (NMR), X-ray diffraction (XRD), and transmission electron microscopy (TEM) were utilized to characterize the high miscibility between PEO and ketoprofen, a model for crystalline drugs with poor water solubility. The experimental data demonstrated that ketoprofen in the melt-processed blend formed a complete molecular dispersion within the amorphous domain of PEO, resulting in high molecular mobility of ketoprofen in the melt-processed blend that leads to enhanced dissolution rate of ketoprofen in aqueous media. Hydrogen bonds between the carboxylic group of ketoprofen and the ether oxygen of PEO, as detected by solid-state NMR, are the likely source for the high miscibility between ketoprofen and PEO. Such drug/polymer molecular interactions promote dispersion of ketoprofen into amorphous phase of PEO at temperatures well below melting points of both crystalline ketoprofen and PEO. Consequently, melt-processing temperatures can be reduced significantly to avoid thermal degradation. The processing conditions can be also flexible while maintaining reproducibility of the physico-chemical properties of the blend. Furthermore, the high degree of drug/polymer molecular interactions stabilizes the morphology of the blend during storage.

Alginate, a natural polysaccharide that has shown great potential as a cell scaffold for the regeneration of many tissues, has only been nominally explored as an electrospun biomaterial due to cytotoxic chemicals that have typically been used during nanofiber formation and crosslinking. Alginate cannot be electrospun by itself and is often co-spun with poly(ethylene oxide) (PEO). In this work, a cell adhesive peptide (GRGDSP) modified alginate (RA) and unmodified alginate (UA) were blended with PEO at different concentrations and blending ratios, and then electrospun to prepare uniform nanofibers. The ability of electrospun RA scaffolds to support human dermal fibroblast cell attachment, spreading, and subsequent proliferation was greatly enhanced on the adhesion ligand-modified nanofibers, demonstrating the promise of this electrospun polysaccharide material with defined nanoscale architecture and cell adhesive properties for tissue regeneration applications.

The effect of fatty acid substitution on the in vitro release of amphotericin B (AmB) from micelles composed of poly(ethylene oxide)-block-poly[N-(6-hexyl stearate)-L-aspartamide] (PEO-b-PHSA) was investigated. PEO-b-PHSA at 11, 50 and 70% of stearic acid substitution self assembled into micelles that effectively encapsulate AmB by solvent evaporation and dialysis methods. The sustained release of AmB from PEO-b-PHSA micelles was evidenced, by measuring the transfer of the drug to lipid vesicles [dipalmitoyl phosphatidylcholine:cholesterol:dimyristoyl phosphatidyglycerol (3:1:0.25)]. The release of AmB for PEO-b-PHSA micelles was markedly influenced by the degree of fatty acid substitution--as it increased, the release of AmB slowed. Accordingly, drug release was found to correlate with haemolysis induced by AmB encapsulated in PEO-b-PHSA micelles. At 11% stearic acid substitution, encapsulation of AmB had little effect on the drug's ability to induce untoward haemolysis. In contrast, AmB stably encapsulated in PEO-b-PHSA micelles at 50 and 70% caused no hemolysis up to 20 microg/ml. Lastly, PEO-b-PHSA micelles at 50 and 70% were able to elute entirely as micelles during size-exclusion chromatography, indicating their stability toward dissociation after dilution. The results point to a nanoscopic drug depot that may release AmB at controlled rates.

Novel amphiphilic diblock copolymers, cholesterol-end-capped poly(2-methacryloyloxyethyl phosphorylcholine) (CMPC), which have poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC)) as hydrophilic segment and cholesterol as hydrophobic segment, was specially designed as drug delivery systems. Fluorescence probe technique and transmission electron microscope (TEM) characterizations indicated that this novel amphiphilic copolymer formed micelles structure in water and the critical micelle concentration (CMC) was determined to be 1.57 x 10(-7) mol/l. A commercial obtained polymeric amphiphiles, Cholesterol end capped PEO (CPEO), which had a similar structure with CMPC, was used as a control in the cytotoxicity test. While CPEO showed obvious cytotoxicity, cytotoxicity of this novel amphiphiles was not observed as indicated by cell culture. Anti-cancer drug adriamycin (ADR) was incorporated into the micelles by oil-in-water method. The size of the drug-containing micelles was less than 200 nm, and the size distribution of the drug-containing micelles showed a narrow and monodisperse unimodal pattern. The release rate of ADR from the nanosphere was slow and the release continued over 7 days and the release rate decreased with the increase of molecular weights of the copolymer and the amount of the drug entrapped. These experimental results suggested that the nanoparticles prepared from CMPC block copolymers could be a good candidate for injectable drug delivery carrier.

OBJECTIVE

To develop multifunctional RGD-decorated poly(ethylene oxide)-b-poly(ester) based micelles and assess their pH-triggered core degradation and targeted drug release in tumor cells that overexpress RGD receptors.

METHODS

Novel poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) based copolymers modified with RGD ligands on PEO and pendent functional groups on PCL, i.e., GRGDS-PEO-b-poly(alpha-benzylcarboxylate-epsilon-caprolactone) (GRGDS-PEO-b-PBCL) and GRGDS-PEO-b-poly(alpha-carboxyl-epsilon-caprolactone) (GRGDS-PEO-b-PCCL), were synthesized. Chemical conjugation of doxorubicin (DOX) to PCCL core produced GRGDS-PEO-b-P(CL-DOX) micellar conjugates, while GRGDS-PEO-b-PBCL were used to physically encapsulate DOX. For both systems, micellar core degradation, drug release, intracellular drug uptake/disposition, and cytotoxicity against B16F10 metastatic cells were investigated.

RESULTS

The PBCL and P(CL-DOX) cores were found resistant to degradation in pH 7.2, but showed 10% and 40% loss in core molecular weight in pH 5.0 within 144 h, respectively. Preferential release of DOX and DOX derivatives from PBCL and P(CL-DOX) cores was noted in pH 5.0, respectively. The GRGDS-modified micelles showed enhanced cellular internalization through endocytosis, increased intracellular DOX release, nuclear localization, and improved cytotoxicity against metastatic B16F10 cells compared to their unmodified counterparts.

CONCLUSIONS

The results clearly suggest a promise for the development of multifunctional polymeric micelles with RGD ligand decorated shell and endosomal pH-triggered degradable core for selective DOX delivery to metastatic cancer cells.

Four-armed (star-branched) block copolymers of l-PLA and PEO were synthesized using ring opening polymerization with different LA/EO ratio. Micellar aggregates were prepared from these block copolymers and characterized. Some surface segregation of PEG was found : the extent depends on the state of the material (whether it is in film or particle form), as well as on molecular geometry. The degradation behavior of star-shaped copolymer was studied over a three week period and compared to its linear counterpart. Anti-cancer drugs 5-FU and paclitaxel were loaded into the micellar nanoparticles. The drug release profile showed that the release of paclitaxel from these polymers could be controlled over 2 weeks. The kinetics of drug release for star-branched, tri- and di-block copolymers were compared. The micelles from star-shaped branch showed more complete release of drug than the diblock copolymers; also, the lower hydrodynamic radius of star-shaped polymers may result in better clearance of the carrier polymer from the body.

A mathematical model is developed to describe the transport phenomena of a water-soluble small molecular drug (caffeine) from highly swellable and dissoluble polyethylene oxide (PEO) cylindrical tablets. Several important aspects in drug release kinetics were taken into account simultaneously in this theoretical model: swelling of the hydrophilic matrix and water penetration, three-dimensional and concentration-dependent diffusion of drug and water, and polymer dissolution. The moving boundary conditions are explicitly derived, and the resulting coupled partial differential equations are solved numerically. In vitro study of swelling, dissolution behavior of PEOs with different molecular weights and drug release are also carried out. When compared with experimental results, this theoretical model agrees with the water uptake, dimensional change and polymer dissolution profiles very well for pure PEO tablets with two different molecular weights. Drug release profiles using this model are predicted with a very good agreement with experimental data at different initial loadings. The overall drug release process is found to be highly dependent on the matrix swelling, drug and water diffusion, polymer dissolution and initial dimensions of the tablets. Their influences on drug release kinetics from PEO with two different molecular weights are also investigated.

Self-assembled nanostructures, such as inverted type mesophases of the cubic or hexagonal geometry or reverse microemulsion phases, can be dispersed using a polymeric stabilizer, such as the PEO-PPO-PEO triblock copolymer Pluronic F127. The particles, which are described in the present study, are based on monolinolein (MLO)-water mixtures. When adding tetradecane (TC) to the MLO-water-F127 system at constant temperature, the internal nanostructure of the kinetically stabilized particles transforms from a Pn3m (cubosomes) to a H2 (hexosomes) and to a water-in-oil (W/O, L2) microemulsion phase (emulsified microemulsion (EME)). To our knowledge, this is the first time that the formation of stable emulsified microemulsion (EME) systems has been described and proven to exist even at room temperature. The same structural transitions can also be induced by increasing temperature at constant tetradecane content. The internal nanostructure of the emulsified particles is probed using small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM). At each investigated composition and temperature, the internal structure of the dispersions is observed to be identical to the corresponding structure of the nondispersed, fully hydrated bulk phase. This is clear evidence for the fact that the self-assembled inner particle nanostructure is preserved during the dispersion procedure. In addition, the internal structure of the particles is in thermodynamic equilibrium with the surrounding water phase. The internal structure of the dispersed, kinetically stabilized particles is a "real" and stable self-assembled nanostructure. To emphasize this fact, we denoted this new family of colloidal particles (cubosomes, hexosomes, and EMEs) as "ISASOMES" (internally self-assembled particles or "somes").

An electrospinning process was successfully used to fabricate polyethylene oxide/cellulose nanocrystal (PEO/CNC) composite nanofibrous mats. Transition of homogeneous to heterogeneous microstructures was achieved by tailoring the concentration of PEO/CNC mixture in the solution from 5 to 7 wt %. Morphology investigation of the obtained nanofibers demonstrated that rod-shaped CNCs were well-dispersed in the as-spun nanofibers and highly aligned along the nanofiber long-axis. PEO/CNC nanofibers became more uniform and smaller in diameter with increased CNC-loading level. The heterogeneous composite mats were composed of rigid-flexible bimodal nanofibers. Results of structure characterization indicated that the incorporated CNCs interacted strongly with the PEO matrix through hydrogen bonding. Mechanical properties of both types of mats were effectively improved by using CNCs, with heterogeneous mats being stronger than their homogeneous counterparts for all compositions (0-20 wt % CNC contents). When a smaller diameter needle was used to form homogeneous mats, enhanced thermal and mechanical properties were obtained.

Poloxamers are triblock copolymers with a center block of hydrophobic polypropylene oxide (PPO) flanked by two hydrophilic polyethyleneoxide (PEO) blocks. Among this family of copolymers, poloxamer 407 is a non-ionic surfactant with reversible gelation properties above a particular polymer concentration and a particular temperature. Easy preparation of poloxamer 407 based sterile injectable formulations have made this copolymer a good candidate for drug delivery, specifically when controlled release of the drug is required. Previously, the applications of compendial poloxamer 407 preparations were demonstrated; however, low viscosity, poor elasticity, and sol-to-gel transition temperature (Tsol-gel) over a wide temperature range were observed. A purification process was introduced to eliminate impurities and low molecular weight copolymer molecules from the compendial poloxamer 407 resulting in higher viscosity values with Tsol-gel in a narrow temperature range. Here, poloxamer 407 was purified based on the proposed process and the rheological and analytical evaluation of the purified poloxamer 407 was conducted and compared to unpurified, compendial poloxamer 407. Then, the impact of poloxamer 407 concentration on gel formation was evaluated. For drug delivery applications, the effect of relevant buffer salts and the effect of addition of ethanol to the poloxamer 407 solutions were rheologically evaluated.

Polymer vesicles, also named polymersomes, are valuable candidates for drug delivery and micro- or nanoreactor applications. As far as drug delivery is concerned, the shape of the carrier is believed to have a strong influence on the biodistribution and cell internalization. Polymersomes can be submitted to an osmotic imbalance when injected in physiological media leading to morphological changes. To understand these osmotic stress-induced variations in membrane properties and shapes, several nanovesicles made of the graft polymer poly(dimethylsiloxane)-g-poly(ethylene oxide) (PDMS-g-PEO) or the triblock copolymer PEO-b-PDMS-b-PEO were osmotically stressed and observed by light scattering, neutron scattering (SANS), and cryo-transmission electron microscopy (cryo-TEM). Hypotonic shock leads to a swelling of the vesicles, comparable to optically observable giant polymersomes, and hypertonic shock leads to collapsed structures such as stomatocytes and original nested vesicles, the latter being only observed for bilayers classically formed by amphiphilic copolymers. Complementary SANS and cryo-TEM experiments are shown to be in quantitative agreement and highlight the importance of the membrane structure on the behavior of these nanopolymersomes under hypertonic conditions as the final morphology reached depends whether or not the copolymers assemble into a bilayer. The vesicle radius and membrane curvature are also shown to be critical parameters for such transformations: the shape evolution trajectory agrees with theoretical models only for large enough vesicle radii above a threshold value around 4 times the membrane thickness.

Drug carriers tailored to fit the physicochemical properties of anticancer agents and the therapeutic peculiarities of tumor management are envisioned for improving the effectiveness/toxicity ratio of the current treatments. Polymeric micelles are attracting much attention owing to their unique beneficial features: i) core-shell structure capable to host hydrophobic drugs, raising the apparent solubility in aqueous medium; ii) size adequate for a preferential accumulation (passive targeting) within the tumor, exhibiting enhanced permeability and retention (EPR effect), and iii) unimers that modulate the activity of efflux pumps involved in multidrug resistance (MDR). This review focuses on amphiphilic poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers, namely the linear poloxamers (Pluronic® or Lutrol®) and the X-shaped poloxamines (Tetronic®), as components of polymeric micelles able to play these three roles. Specific facets of poloxamers have been highlighted some years ago, but recently their wide range of possibilities is beginning to be fully elucidated and understood. Poloxamines are new excipients in the cancer arena and the comparison of their performance with that of poloxamers may enable to identify aspects of their architecture relevant for the optimization of micellar carriers. Clinical trials in progress indicate that drug-loaded polymeric micelles are beneficial regarding efficiency, safety, and compliance of the treatment and quality of life of the patients. The fact that some copolymers are already approved for internal use and several chemotherapy agents will be off patent soon may help to bring the clinical use of poloxamer- or poloxamine-based micelles into a reality in the coming years.

Due to the persistent spread of antibiotic resistance, commercial antibiotic treatments are proving ineffective. Cinnamaldehyde (CA), a volatile essential oil, eradicates pathogens non-specifically. However, the ability to incorporate essential oils into nanofiber mats has not yet been demonstrated, and, only six studies have electrospun two immiscible phases. Here, CA (0.5 and 5.0%) was incorporated into chitosan/poly(ethylene oxide) (PEO) solutions that were successfully electrospun into mats with ∼ 50 nm fiber diameters. Solid-state NMR results corroborated with release studies wherein the 5.0% CA mats released a statistically higher amount of CA-liquid (545% more) and CA-vapor (279% more) than the 0.5% CA mats. In time dependent cytotoxicity studies, the intrinsic antibacterial activity of chitosan along with the quick release of CA enabled high inactivation rates against Escherichia coli and Pseudomonas aeruginosa. For the first time we have demonstrated chitosan/CA/PEO nanofiber mats can serve as CA delivery vehicles that potentially eradicate pseudomonas infections.

Beyond state-of-the-art lithium-ion battery (LIB) technology with metallic lithium anodes to replace conventional ion intercalation anode materials is highly desirable because of lithium's highest specific capacity (3,860 mA/g) and lowest negative electrochemical potential (∼3.040 V vs. the standard hydrogen electrode). In this work, we report for the first time, to our knowledge, a 3D lithium-ion-conducting ceramic network based on garnet-type Li6.4La3Zr2Al0.2O12 (LLZO) lithium-ion conductor to provide continuous Li(+) transfer channels in a polyethylene oxide (PEO)-based composite. This composite structure further provides structural reinforcement to enhance the mechanical properties of the polymer matrix. The flexible solid-state electrolyte composite membrane exhibited an ionic conductivity of 2.5 × 10(-4) S/cm at room temperature. The membrane can effectively block dendrites in a symmetric Li | electrolyte | Li cell during repeated lithium stripping/plating at room temperature, with a current density of 0.2 mA/cm(2) for around 500 h and a current density of 0.5 mA/cm(2) for over 300 h. These results provide an all solid ion-conducting membrane that can be applied to flexible LIBs and other electrochemical energy storage systems, such as lithium-sulfur batteries.

The essential oils (EO) of Mentha suaveolens, a wild Labiatae, which grows in several regions in Morocco, were characterized and their antimicrobial activity assessed. The main aromatic constituents of this plant, as characterized by IR, NMR and MS studies, were pulegone, piperitenone oxide (PEO) and piperitone oxide (PO) occurring in different amounts depending on the subspecies. These constituents as well as a series of other aromatic products such as carvone, limonene and menthone, were tested for their antimicrobial activity against 19 bacteria including Gram-positive and Gram-negative and against three fungi, using solid phase and microtitration assays. Pulegone-rich essential oil inhibited efficiently all the micro-organisms tested with MICs ranging between 0.69 and 2.77 ppm. Among the components from Mentha suaveolens EO, pulegone was the most effective against the tested microorganisms, followed by PEO and PO. The structure-activity relationship is discussed on the basis of the activity of the other aromatic derivatives tested such as carvone, limonene, menthone and the profile of the essential oils of Mentha suaveolens was compared with other Mentha species.

The biocompatibility of ABA triblock copolymers consisting of poly(L-lactide-co-glycolide) A blocks attached to a central poly(ethylene oxide), (PEO), B block was investigated under in vitro conditions. The ABA triblock copolymer was compared to commercially available Poly(D,L-lactide-co-glycolide) (PLGA) and reference materials in different L929 cell culture models according to the procedure recommended by the International Standard Organization (ISO). Different preparation methods: namely extraction, indirect contact and direct contact with polymer samples were compared. The extraction method seems to be the most sensitive assay, allowing estimates of IC50 values. ABA and PLGA polymers showed excellent compatibility with L929 fibroblasts with all preparation techniques used. The influence of polymer composition and molecular weight on degradation rate as well as in vitro biocompatibility was then investigated. Changes in pH and osmolarity as well as lactic acid content of the extracts were determined and compared to in vitro degradation data of polymer films in phosphate buffered saline at 37 degreesC evaluating molecular weight (GPC) and massloss (gravimetry). An acceleration of the degradation rate of the ABA triblock copolymers with increasing PEO content was observed. The in vitro cytotoxicity studies demonstrated that the three ABA polymers were well tolerated by fibroblasts in cell culture. One ABA polymer batch ABA2 showed unusual in vitro cytotoxicity in L929 fibroblasts, possibly related to the molecular weight of the PEO used for this particular batch or residual glycolic acid. Cell culture models for biocompatibility testing of polymers according to ISO are useful as screening models in characterizing biodegradable polymers, but they cannot replace animal testing. The extraction method in combination with the MTT assay allows quantitative ranking of cytotoxic properties with high sensitivity.

BACKGROUND

Health sciences programs are increasingly expanding their curricula to bridge foundational scientific knowledge with needed skills to practice and patient care. The primary objectives of this study are to 1) assess whether the personal and professional development (PPD) subdomains (self-assessment, leadership, innovation and entrepreneurship, and professionalism) are integrated in a pharmacy curriculum; and 2) identify any gaps related to the subdomains' learning objectives.

METHODS

Four different mapping activities were completed to create a comprehensive mapping plan regarding the integration of the PPD subdomains in the curriculum. The first mapping activity entailed matching the school's program educational outcomes (PEOs) to these subdomains (Step 1). Mapping of the enacted curriculum by faculty (Step 2) and learned curriculum by students (Step 3) were also completed in order to evaluate the integration of these subdomains in the curriculum. Finally, Step 4 involved mapping of the assessed curriculum by analyzing the progress of students on PPD-related competencies using standardized scoring rubrics and the correlation between students' and facultys' assessments with regard to matching competencies. The Cochrane's Q test and the Cohen's kappa coefficient were used in the statistical analysis of parametric data.

RESULTS

The subdomains were found to be woven across curricular, co-curricular, and extra-curricular activities based on the four different mapping activities. Faculty and students agreed that the PPD competencies are integrated in the curriculum; provided example courses, experiences and activities; and identified areas of further improvements. The completed mapping activities drove the development of action plans for remediation of identified gaps in the curriculum.

CONCLUSIONS

Mapping activities showed the sequential integration of the PPD skills at different depths and breadths in the curriculum. This study provides an example to health sciences schools on the incorporation of the PPD skills in their curricular, co-curricular and extra-curricular activities as current accreditation standards have directed Pharmacy programs to integrate and enforce them in their curricula.

We report on the fabrication of photochromic polymersomes exhibiting photoswitchable and reversible bilayer permeability from newly designed poly(ethylene oxide)-b-PSPA (PEO-b-PSPA) diblock copolymers, where SPA is spiropyran (SP)-based monomer containing a unique carbamate linkage. Upon self-assembling into polymersomes, SP moieties within vesicle bilayers undergo reversible phototriggered isomerization between hydrophobic spiropyran (SP, λ2>> 450 nm irradiation) and zwitterionic merocyanine (MC, λ1 < 420 nm irradiation) states. For both SP and MC polymersomes, their microstructures are stabilized by multiple cooperative noncovalent interactions including hydrophobic, hydrogen bonding, π-π stacking, and paired electrostatic (zwitterionic) interactions, with the latter two types being exclusive for MC polymersomes. Control experiments using analogous block copolymers of hydrophobic SP monomer with a carbonate linkage (SPO) and conventional spiropyran methacrylate monomer (SPMA) containing a single ester functionality were then conducted, revealing that carbamate-incurred hydrogen bonding interactions in PEO-b-PSPA are crucial for polymersome stabilization in the zwitterionic MC state. Moreover, reversible phototriggered SP-to-MC polymersome transition is accompanied by membrane polarity and permeability switching from being nonimpermeable to selectively permeable toward noncharged, charged, and zwitterionic small molecule species below critical molar masses. Intriguingly, UV-actuated MC polymersomes possess two types of release modules: (1) sustained release upon short UV irradiation duration by taking advantage of the unexpectedly slow spontaneous MC-to-SP transition kinetics (t1/2>> 20 h) under dark conditions; (2) on-demand and switchable release under alternated UV-vis light irradiation. We further demonstrate photoswitchable spatiotemporal release of 4',6-diamidino-2-phenylindole (DAPI, cell nuclei-staining dye) within living HeLa cells.

Background Migraine is a well-known feature of mitochondrial disorders (MDs). However, no systematic epidemiological data are available in large populations of patients. Aims The aim of this cross-sectional cohort study was to describe the prevalence and migraine characteristics in a large cohort of patients with mitochondrial encephalomyopathies. Methods We studied 93 consecutive patients with characterised MDs referred to our Neuromuscular Unit during a 12-month period. All patients (age range = 16-78 years; 31 men; 58 progressive external ophthalmoplegia [PEO], 12 myoclonic epilepsy with ragged red fibres [MERRF], eight mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes [MELAS], two mitochondrial neurogastrointestinal encephalomyopathy [MNGIE] and 13 other MDs) underwent a structured diagnostic headache interview using an operational diagnostic tool following the IHS criteria. If they met the criteria for migraine, they were included in the 'Migraine Group'. The other patients were counted in the 'No Migraine Group'. Patient demographic and migraine characteristics were examined. Clinical, neuroradiological and neurophysiological data were compared between groups. Results Migraine was reported in 35.5% of patients. Migraine without aura was the most common headache (81.8%). The migraine group showed younger age ( P < 0.01), increased prevalence of epilepsy ( P = 0.01), myoclonus ( P = 0.03), stroke-like episodes ( P = 0.03) and decreased prevalence of muscle weakness ( P < 0.01). Multivariate analysis showed that migraine was positively associated with absence of muscle weakness ( P = 0.04) and presence of EEG abnormalities ( P = 0.02). Conclusion Migraine has a higher prevalence in MDs compared with general population-based data, independently from genotype or phenotype. Migraine is not merely a phenotypic aspect of specific MDs but is rather the expression of vulnerability of the central nervous system, probably directly related with defects of the respiratory chain.

Over 100 pathogenic point mutations and 200 deletions, insertions, and rearrangements have been identified since the first mitochondrial DNA mutations were described in 1988. About 60% of the point mutations affect mitochondrial tRNAs, 35% affect polypeptide subunits of the respiratory chain, and 5% affect mitochondrial ribosomal RNAs. The clinical phenotypes of mitochondrial tRNA disease span the spectrum of all known oxidative phosphorylation disorders and include MELAS, MERRF, Leigh syndrome, PEO, deafness, diabetes, sideroblastic anemia, myoclonus, skeletal myopathy, cardiomyopathy, and renal tubular acidosis. Mutations in respiratory chain proteins encoded by mtDNA result in phenotypes ranging from exercise intolerance to blindness, ataxia, dystonia, dementia, and Leigh syndrome.

CONCLUSIONS

The primary disorders of oxidative phosphorylation are commonly associated with a delayed age of onset, organ selectivity, and an episodic, progressive course. Organ-specific, non-ATP related functions of mitochondria are discussed as important considerations in evaluating the pathogenesis of mitochondrial disease.