Metastatic paraplegia and vital prognosis: perspectives and limitations for rehabilitation care. Part 1

Fattal C, Fabbro M, Gelis A, Bauchet L. Metastatic paraplegia and vital prognosis: perspectives and limitations for rehabilitation care. Part 1.

Objective

To evaluate the vital prognosis of patients with metastatic epidural spinal cord compression (MESCC) to determine the relevance and duration of physical medicine and rehabilitation (PM&R) admission.

Data Sources

Publications from 1980 to January 2010 selected from 3 databases.

Study Selection

Publications reporting data correlated with survival and prognosis factors, highlighting publications with level A scientific evidence (prospective randomized controlled studies with significant casuistry and relevant judgment criteria). The work focused on patients with MESCC below T1.

Data Extraction

Standardized reading grid.

Data Synthesis

Thirty-eight studies met the inclusion criteria. Most were retrospective. For survival rate at 1 year, they reported data ranging from 12% to 58%. The 12-month and median survival rates were the data reported most often in the articles. The median survival rate ranged from 2.4 to 30 months, and 12-month survival rates ranged from 12% to 58%. Of publications that chose this parameter, 95% reported 12-month survival rates less than 55.2% (95th percentile) regardless of patients' functional status and associated risk factors (eg, location of primary cancer, metastases spreading, pretreatment ambulatory status).

Conclusions

Despite major progress in cancer care, patients with MESCC still have a limited vital prognosis. The relevance and duration of PM&R care must be evaluated against the patient's functional need for rehabilitation while making time for family. The hypothesis of a 1-month stay extended only once appears reasonable for patients to adapt to their new functional status without taking precious time away from their loved ones.     

An antibody profile of systemic lupus erythematosus detected by antigen microarray

Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self‐antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self‐antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states – SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long‐term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double‐stranded DNA (dsDNA), single‐stranded DNA (ssDNA), Epstein–Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin‐like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.     

A new paradigm for high‐sensitivity 19F magnetic resonance imaging of perfluorooctylbromide

In the present work, the NMR properties of perfluorooctylbromide are revisited to derive a high‐sensitivity fluorine MRI strategy. It is shown that the harmful effects of J‐coupling can be eliminated by carefully choosing the bandwidth of the 180° pulses in a spin‐echo sequence. The T₂ of the CF₃ resonance of the molecule is measured using a multispin‐echo sequence and shown to dramatically depend on the interpulse delay. Following these observations, an optimized multispin‐echo imaging sequence is derived and compared with short TE/pulse repetition time gradient echo and chemical shift imaging sequences. The unparalleled sensitivity yielded by the multispin‐echo sequence is promising for future applications, in particular for targeted contrast agents such as perfluorooctylbromide nanoparticles. Magn Reson Med 63:1119–1124, 2010. © 2010 Wiley‐Liss, Inc.     

Downregulation of endotoxin-induced uveitis by intravitreal injection of vasoactive intestinal Peptide encapsulated in liposomes

PURPOSE: To reestablish the immunosuppressive microenvironment of the eye, disrupted by ocular inflammation during endotoxin-induced uveitis (EIU), by means of intravitreal injection of vasoactive intestinal peptide (VIP) in saline or encapsulated in liposomes, to increase its bioavailability and efficiency. METHODS: EIU was induced in Lewis rats by subcutaneous injection of lipopolysaccharide (LPS). Simultaneously, animals were intravitreally injected with saline, saline/VIP, VIP-loaded liposomes (VIP-Lip), or unloaded liposomes. EIU severity and cellular infiltration were assessed by clinical examination and specific immunostaining. VIP concentration was determined in ocular fluids by ELISA. Ocular expression of inflammatory cytokine and chemokine mRNAs was detected by semiquantitative RT-PCR. Biodistribution of rhodamine-conjugated liposomes (Rh-Lip) was analyzed by immunohistochemistry in eyes and regional cervical lymph nodes (LNs). RESULTS: Twenty-four hours after intravitreal injection of VIP-Lip, VIP concentration in ocular fluids was 15 times higher than after saline/VIP injection. At that time, EIU clinical severity, ocular infiltrating polymorphonuclear leukocytes (PMNs), and, to a lesser extent, ED1(+) macrophages, as well as inflammatory cytokine and chemokine mRNA expression, were significantly reduced in VIP-Lip-injected rats compared with rats injected with saline/VIP, unloaded liposomes, or saline. Rh-Lip was distributed in vitreous, ciliary body, conjunctiva, retina, and sclera. It was internalized by macrophages and PMNs, and VIP colocalized with liposomes at least up to 14 days after injection. In cervical LNs, resident macrophages internalized VIP-Rh-Lip, and some adjacent lymphocytes showed VIP expression. CONCLUSIONS: VIP was efficient at reducing EIU only when formulated in liposomes, which enhanced its immunosuppressive effect and controlled its delivery to all tissues affected by or involved in ocular inflammation.     

Novel microparticulate system made of poly(methylidene malonate 2.1.2).

Formulation of PMM 2.1.2 microparticles entrapping ovalbumin as a model protein was achieved by using a double emulsion solvent evaporation method. Parameters such as the nature of the solvent, polymer concentration and polymer molecular weight were investigated. Preparation process led to the formation of spherical and smooth particles with a mean diameter of 5 microm, and an encapsulation efficiency and protein loading level of up to 16 and 2.9% w/w, respectively. After an initial burst of approximately 10%, the protein was released at a rate of less than 1% per day. This slow release kinetics of encapsulated ovalbumin in phosphate buffer indicates that most of the protein was encapsulated within the polymer matrix. Degradation of PMM 2.1.2 microparticles in the presence of esterases indicated that side chain hydrolysis of the polymer was the rate-determining step in bioerosion; cleavage of the ester side chain, which was further hydrolyzed to glycolic acid and ethanol, led to an acrylic acid and subsequent solubilization of the polymer. However, slow polymer backbone solubilization after degradation was observed.     

Hydrosoluble polymers for muscular gene delivery

Striated muscle tissue is an attractive target for gene delivery as it can be easily reached and can express exogenous proteins. However, administration of naked DNA results in low transfection levels, and the design and development of safe and efficient gene delivery systems are thus required.This review is focusing on the characteristics of the striated muscle tissue with regards to features possibly affecting gene transfer, as well as the different soluble polymers that have been evaluated as gene carriers. The described formulations are ranging from polymers displaying a high density of positive charges to non-ionic molecules. Nevertheless, polymers exhibiting few or no positive charges appear to our opinion as the most promising approach to achieve both safe and efficient transfection of the striated muscles.     

Biocompatible poly(methylidene malonate)-made materials for pharmaceutical and biomedical applications.

In the past 20 years, mainly with the sponsorship of Laboratoires UPSA (France) and, afterwards, its spin-off company Virsol (France), several authors have studied methylidene malonate-based polymers used in drug delivery approaches and in the development of novel biomaterials. The present paper aims at summing up the preparation of methylidene malonate monomers, and essentially a novel asymmetric diester structure: 1-ethoxycarbonyl-1-ethoxycarbonylmethylenoxycarbonyl ethene named methylidene malonate 2.1.2. Their polymeric and copolymeric derivatives and a few of their applications which were reported in the literature are also presented. It encompasses the manufacturing of particulate systems such as nano- and macroparticles designed for the delivery of hydrophilic or hydrophobic drugs and biomolecules. This review article also describes their use as biomaterials of interest in the fields of tissue repair, as drug reservoirs or ophthalmology, as implants. Copolymers based on these monomers offer a large range of properties and could be used as new surfactants, micellar vectors, or particulate systems for gene delivery. Therefore, this review, certainly the first dedicated exclusively to methylidene malonate-based materials, highlights the great biomedical and pharmaceutical technology potential of these new materials.     

Oligonucleotide-Polyethylenimine Complexes Targeting Retinal Cells: Structural Analysis and Application to Anti-TGFβ-2 Therapy

Purpose The aim of this study was to characterize oligonucleotide–polyethylenimine (ODN/PEI) complex preparation for potential transfection of retinal cells in vitro and in vivo. Methods The effect of medium preparation [HEPES-buffered saline (HBS), water] on particle size and morphology was evaluated. Cultured Lewis rat retinal Müller glial (RMG) cells were transfected using fluorescein isothiocyanate (FITC)–ODN/PEI complexes specifically directed at transforming growth factor beta (TGFβ)-2. Efficacy of transfection was evaluated using confocal microscopy, and regulation of gene expression was assayed using quantitative real-time RT-PCR and ELISA assay. One, 24, and 72 h after injection of FITC–ODN/PEI complexes into the vitreous of rat eyes, their distribution was analyzed on eye sections. Results Complexes prepared in HBS were smaller than complexes prepared in pure water and presented a core–shell structure. These particles showed a high cellular internalization efficacy, along with a significant and specific down-regulation of TGFβ-2 expression and production in RMG cells, correlating with specific inhibition of cell growth at 72 h. In vivo, complexes efficiently transfect retinal cells and follow a transretinal migration at 24 h. After 72 h, ODN seems to preferentially target RMG cells without inducing any detectable toxicity. Conclusions Specific down-regulation of TGFβ-2 expression using ODN/PEI complexes may have potential interest for the treatment of retinal diseases associated with glial proliferation.     

Morphology, structure and supramolecular organization of hybrid 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine–hyaluronic acid microparticles prepared by spray drying

We characterized the morphology, structure and supramolecular organization of microparticles obtained by spray drying 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and hyaluronic acid (HA). Pure DPPC microparticles are small and strongly aggregated with phospholipids organized in a lamellar-like structure observable by scanning electron microscopy (SEM). X-ray scattering demonstrates that it corresponds to an almost dry lamellar phase with chains tilted with respect to the bilayer surface and organized according to a hexagonal lattice within the bilayer. Upon aging, DPPC reorganizes into an orthorhombic structure within the bilayer. The addition of HA leads to an increase of particle size and a decrease of aggregation and tap density associated to a morphology switch from dense spheres to hollow shells. By contrast, the supramolecular organization is not modified: HA is mostly “sandwiched” between DPPC headgroups. In addition, HA impedes phospholipids rearrangement upon aging. Altogether, for drug delivery purposes, the addition of HA is beneficial in terms of stability and physical properties.     

Cationic nanoemulsion as a delivery system for oligonucleotides targeting malarial topoisomerase II

A promising strategy based on the antisense oligonucleotides against the Plasmodium falciparum topoisomerase II has been considered using cationic nanoemulsion as oligonucleotide delivery system. Phosphodiester and chemically modified phosphorothioate oligonucleotides bearing negative charges were adsorbed on positively charged emulsion composed of medium chain triglycerides, egg lecithin, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and water, at different +/− charge ratios (positive charges from cationic lipid/negative charges from oligonucleotide): +0.5/−, +2/−, +4/− and +6/−. The physicochemical properties of the complexes were determined, as well as their stability in culture medium. Their interaction with erythrocytes through hemolysis, binding experiments and confocal microscopy were also evaluated. Finally, the in vitro evaluation of parasite growth and reinfection capacity was performed. The overall results showed that antisense oligonucleotides against P. falciparum topoisomerase II gene can be efficiently adsorbed onto a cationic nanoemulsion forming complexes. Whereas unloaded nanoemulsion displayed an hemolytic effect due to the presence of the cationic lipid, this was not the case of loaded nanoemulsion at low +/− ratios. Oligonucleotide-loaded nanoemulsions were found to be located inside the infected erythrocytes, inhibiting efficiently parasite growth (until 80%) and causing a delay in P. falciparum life cycle.