To successfully prevent secondary health conditions (SHCs) and promote longevity after spinal cord injury (SCI), we must first understand the risk factors precipitating their occurrence and develop strategies to address these risk factors. Conceptual models may aid in identifying the nature of SHCs and guide research, clinical practice, and the development of prevention strategies.
Our purpose is to review and refine an existing theoretical risk and prevention model (TRPM) as a means of classifying risk and protective factors for SHCs and mortality after SCI and for identifying points of intervention.
We describe conceptual work within the field of SCI research and SHCs, including a description of the TRPM, a review of research using the TRPM, and conceptual enhancements to the TRPM based on previous research.
The enhanced TRPM directs research to the timing and chronicity of the SHCs and their relationship with overall health and physiologic decline. Future research should identify differences in the nature of SHCs, the extent to which they relate to risk and protective factors, and the degree to which they may be prevented with appropriate research-based strategies.
health; longevity; mortality; risk; spinal cord injury; theoretical models
Transferrin (Tf) conjugated lipopolyplexes (LPs) carrying G3139, an antisense oligonucleotide for Bcl-2, were synthesized and evaluated in Tf receptor positive K562 erythroleukemia cells and then in a murine K562 xenograft model.
Materials and Methods
Particle size and Zeta potentials of transferrin conjugated lipopolyplexs containing G3139 (Tf-LP-G3139) were measured by Dynamic Light Scattering and ZetaPALS. In vitro and in vivo sample’s Bcl-2 downregulation was analyzed using Western blot and tumor tissue samples also exhibited by immunohistochemistry method. For athymic mice bearing with K562 xenograft tumors, tumor growth inhibition and survival rate were investigated. Nanoparticle distribution in 3-D cell cluster was observed by Laser scan confocal microscopy. IL-12 production in the plasma was measured by ELISA kit.
In vitro, Tf-LP-G3139 was more effective in inducing down regulation of Bcl-2 in K562 cells than non-targeted LP-G3139, free G3139 and mismatched control ODN-G4126 in the same formulation. In vivo Tf-LP-G3139 was less effective than free G3139 in Bcl-2 down regulation. 3-D cell cluster model diffusion results indeed indicated limited penetration of the LPs into the cell cluster. Finally, the therapeutic efficacies of Tf-LP-G3139 and free G3139 were determined in the K562 xenograft model. Tf-LP-G3139 showed slower plasma clearance, higher AUC, and greater accumulation in the tumor compared to free G3139. In addition, Tf-LP-G3139 was found to be more effective in tumor growth inhibition and prolonging mouse survival than free G3139. This was associated with increased spleen weight and IL-12 production in the plasma.
The role of the immune system in the therapeutic response obtained with the Tf-LPs is necessary and in vitro 3-D cell cluster model can be a potential tool to evaluate the nanoparticle distribution.
Bcl-2; leukemia; lipopolyplexs; targeted drug delivery; transferrin receptor
Oligonucleotides (ONs) have shown great promise as therapeutic agents for various diseases. It is necessary to provide a protocol for preparation of ON-loaded lipid nanoparticles (LNPs) in a reproducible manner on a laboratory scale.
Materials and Methods
A 3-inlet microfluidic (MF) chip-based device was used to synthesize LNPs at the lipid/ON ratio of 10/1 (w/w) and at flow rates ranging from 50 to 1100 µl/min. A series of LNPs containing either antisense oligodeoxyribonucleotide (AS-ODN) or small-interfering RNA (siRNA) were synthesized. Bulk mixing was used as control.
The MF method was shown to be particularly useful for synthesis of LNPs loaded with AS-ODN. The optimal range of flow rates for AS-ODN LNPs was found to be 100 to 200 µl/min. MF synthesis produced LNPs with lower polydispersity values. However, the MF was less effective in preparing LNPs loaded with siRNA, which may have been due to greater rigidity of double-stranded siRNA comparing to single-stranded AS-ODN.
MF technology is a simple, affordable and reproducible method for production of ON-LNPs.
Microfluidics; oligonucleotide; lipid nanoparticles
Liposomes are composed of lipid bilayer membranes that encapsulate an aqueous volume. A major challenge in the development of liposomes for drug delivery is the control of size and size distribution. In conventional methods, lipids are spontaneously assembled into heterogeneous bilayers in a bulk phase. Additional processing by extrusion or sonication is required to obtain liposomes with small size and a narrow size distribution. Microfluidics is an emerging technology for liposome synthesis, because it enables precise control of the lipid hydration process. Here, we describe a number of microfluidic methods that have been reported to produce micro/nanosized liposomes with narrower size distribution in a reproducible manner, focusing on the use of continuous-flow microfluidics. The advantages of liposome formation using the microfluidic approach over traditional bulk-mixing approaches are discussed.
Disulfide-linked oligodeoxyribonucleotide (ODN) liposomes were formulated and evaluated for the delivery of antisense ODN G3139 in KB human oral carcinoma cells.
Materials and Methods
Liposomes composed of 1,2-di-(9Z-octadecenoyl)-3-trimethylammo-nium-propane (DOTAP)/egg phosphatidylcholine/α-tocopheryl polyethylene glycol 1000 succinate were incorporated with hydrophobized disulfide-linked ODN. Disulfide-linked ODN liposomes were characterized for their size, ODN intracellular delivery, Bcl-2 mRNA and protein expression, growth inhibition, and chemosensitization.
Intracellular delivery of ODN with disulfide-linked ODN liposomes was more efficient than that with non-liposomal hydrophobized disulfide-linked ODN. Treatment of the cells with disulfide-linked ODN liposomes resulted in efficient Bcl-2 down-regulation greater than that with hydrophobized disulfide-linked ODN and consistent with that of cellular growth inhibition and the sensitization to daunorubicin in KB cells. Disulfide-linked ODN liposomes exhibited superior colloidal stability during 5-week storage.
Disulfide-linked liposomes are effective delivery vehicles for antisense ODN.
Liposomes; disulfide; antisense oligonucleotide; G3139; Bcl-2; drug delivery
Efficient and site-specific delivery of therapeutic drugs is a critical challenge in clinical treatment of cancer. Nano-sized carriers such as liposomes, micelles, and polymeric nanoparticles have been investigated for improving bioavailability and pharmacokinetic properties of therapeutics via various mechanisms, for example, the enhanced permeability and retention (EPR) effect. Further improvement can potentially be achieved by conjugation of targeting ligands onto nanocarriers to achieve selective delivery to the tumour cell or the tumour vasculature. Indeed, receptor-targeted nanocarrier delivery has been shown to improve therapeutic responses both in vitro and in vivo. A variety of ligands have been investigated including folate, transferrin, antibodies, peptides and aptamers. Multiple functionalities can be incorporated into the design of nanoparticles, e.g., to enable imaging and triggered intracellular drug release. In this review, we mainly focus on recent advances on the development of targeted nanocarriers and will introduce novel concepts such as multi-targeting and multi-functional nanoparticles.
Drug delivery; nanocarriers; drug targeting
Liposomes have been successfully used as delivery vehicles for anticancer drugs. Both sonication and microfluidic technologies have been used to produce liposomes. The combination of the two methods was evaluated in this study.
Materials and Methods
The microfluidic devices, mainly comprising micro-dispensers and a sonicator, were used to produce liposomal nanoparticles. Sonication was used to enhance the reduction of liposome size.
Sonication significantly reduced the size of the liposomes. The particle size also decreased as the buffer to solvent flow rate ratio increased. The smallest particle sizes were achieved with a volumetric flow rate of lipids at 0.374 ml/min.
The microfluidic devices in combination with ultrasound are simple and may be used to produce liposomal nanoparticles with narrow size distribution.
Liposomes; microfluidics; ethanol injection; sonication
While calcium-phosphate has been used to deliver plasmid DNA (pDNA) for decades, the method is typically characterized by low and irreproducible transfection efficiency relative to the other non-viral approaches, such as liposomes and polymers. Here we report a novel gene transfer vector comprising lipid-coated nano-calcium-phosphate (LNCP) that provides consistently efficient and satisfactory pDNA delivery. It is based on core-shell nanoparticles comprising a calcium-phosphate core and a cationic lipid shell. This method, in contrast to the solution precipitation methods used in the past, yields colloidally stable calcium-phosphate nanoparticles inside the cationic liposomes. Our results indicate that the particle size and the size distribution of the LNCP remain virtually unchanged even after 21 days of storage. Atomic force microscopy measurements reveal that the LNCP have a 5-fold higher rigidity than common cationic liposomes. The LNCP transfected pDNA 24 times greater than the naked pDNA and 10-fold greater relative to the standard calcium-phosphate precipitation preparations, suggesting that the LNCP may have potential as a novel transfection agent for gene therapy.
Nanoparticles; Cationic liposome; Calcium-phosphate; Gene therapy
Herein we describe the development and implementation of a nanoporous cell-therapy device with controllable biodegradation. Dopamine-secreting PC12 cells were housed within newly formulated alginate-glutamine degradable polylysine (A-GD-PLL) microcapsules. The A-GD-PLL microcapsules provided a 3-D microenvironment for good spatial cell growth, viability and proliferation. The microcapsules were subsequently placed within a poly(ethylene glycol) (PEG)-coated poly(ε-caprolactone) (PCL) chamber covered with a PEG-grafted PCL nanoporous membrane formed by phase inversion. To enhance PC12 cell growth and to assist in controlled degradation of both the PC12 cells and the device construct, small PCL capsules containing neural growth factor (PCL-NGF) and a poly(lactic-co-glycolic acid) pellet containing glutamine (PLGA-GLN) were also placed within the PCL chamber. Release of NGF from the PCL-NGF capsules facilitated cell proliferation and viability, while the controlled release of GLN from the PLGA-GLN pellet resulted in A-GD-PLL microcapsule degradation and eventual PC12 cell death following a pre-specified period of time (4 weeks in this study). In vivo, our device was found to be well tolerated and we successfully demonstrated the controlled release of dopamine over a period of four weeks. This integrated biodegradable device holds great promise for the future treatment of a variety of diseases.
Nanoporous capsules; Controllable biodegradation; Glutamine-degradable PLL microcapsules; Neural growth factor; Dopamine secretion
Histone deacetylase (HDAC) inhibitors either alone or in combination with hypomethylating agents have limited clinical effect in acute myeloid leukemia (AML). Previously we demonstrated that AML patients with higher miR-29b expression had better response to the hypomethylating agent decitabine. Therefore, an increase in miR-29b expression preceding decitabine treatment may provide a therapeutic advantage. We previously showed that miR-29b expression is suppressed by a repressor complex that includes HDACs. Thus, HDAC inhibition may increase miR-29b expression. We hypothesized that priming AML cells with the novel HDAC inhibitor (HDACI) AR-42 would result in increased response to decitabine treatment via upregulation of miR-29b. Here we show that AR-42 is a potent HDACI in AML, increasing miR-29b levels and leading to downregulation of known miR-29b targets (i.e., SP1, DNMT1, DNMT3A, and DNMT3B). We then demonstrated that the sequential administration of AR-42 followed by decitabine resulted in a stronger anti-leukemic activity in vitro and in vivo than decitabine followed by AR-42 or either drug alone. These preclinical results with AR-42 priming before decitabine administration represents a promising, novel treatment approach and a paradigm shift with regard to the combination of epigenetic-targeting compounds in AML, where decitabine has been traditionally given before HDAC inhibitors.
acute myeloid leukemia; HDACI; AR-42; decitabine; miR-29b
Clinical application of small interfering RNA (siRNA) requires safe and efficient delivery in vivo. Here, we report the design and synthesis of lipid nanoparticles (LNPs) for siRNA delivery based on cationic lipids with multiple tertiary amines and hydrophobic linoleyl chains. LNPs incorporating the lipid containing tris(2-aminoethyl)amine (TREN) and 3 linoleyl chain, termed TRENL3, were found to have exceptionally high siRNA transfection efficacy that was markedly superior to lipofectamine, a commercial transfection agent. In addition, inclusion of polyunsaturated fatty acids, such as linoleic acid and linolenic acids in the formulation further enhanced the siRNA delivery efficiency. TRENL3 LNPs were further shown to transported siRNA into the cytosol primarily via macropinocytosis rather than clathrin-mediated endocytosis. The new LNPs have demonstrated preferential uptake by the liver and hepatocellular carcinoma in mice, thereby leading to high siRNA gene silencing activity. These data suggest potential therapeutic applications of TRENL3 mediated delivery of siRNA for liver diseases.
Cationic lipids; Lipid nanoparticles; Small interfering RNA; hepatocellular carcinoma
The Hedgehog signaling pathway is linked to a variety of diseases, notably a range of cancers. The first generation of drug screens identified Smoothened (Smo), a membrane protein essential for signaling, as an attractive drug target. Smo localizes to the primary cilium upon pathway activation, and this transition is critical for the response to Hedgehog ligands. In a high content screen directly monitoring Smo distribution in Hedgehog responsive cells, we identified different glucocorticoids as specific modulators of Smo ciliary accumulation. One class promoted Smo accumulation, conferring cellular hypersensitivity to Hedgehog stimulation. In contrast, a second class inhibited Smo ciliary localization and signaling activity by both wildtype Smo, and mutant forms of Smo, SmoM2 and SmoD473H, that are refractory to previously identified Smo antagonists. These findings point to the potential for developing glucocorticoid-based pharmacological modulation of Smo signaling to treat mutated drug-resistant forms of Smo, an emerging problem in long-term cancer therapy. They also raise a concern about potential crosstalk of glucocorticoid drugs in the Hedgehog pathway, if therapeutic administration exceeds levels associated with on-target transcriptional mechanisms of glucocorticoid action.
Klebsiella pneumoniae PR04 was isolated from a patient hospitalized in Malaysia. The draft genome sequence of K. pneumoniae PR04 shows differences compared to the reference sequences of K. pneumoniae strains MGH 78578 and NTUH-K2044 in terms of their genomic structures.
DOTAP, as a racemic mixture, is a cationic lipid and a widely used transfection reagent. In this study, the effect of DOTAP’s stereochemical structure on transfection efficiency was evaluated in vitro. Racemic and enantiomerically pure DOTAP were used in lipoplex formulations to deliver siRNA to MCF-7 cells, targeting the aromatase enzyme. At the 50nM siRNA concentration and lipid-to-RNA charge ratios of 4 and 5, the R enantiomer of DOTAP was found to perform better than either the S- and the racemic agent. In addition, at 10 nM siRNA concentration and a charge ratio of 3, the R- lipoplex formulation silenced aromatase by ~ 50% whereas the S and racemic formulations caused no significant target downregulation. Differences in lipid packing were modeled using membrane simulations. The results showed that, when combined with cholesterol, pure R-DOTAP and S-DOTAP enantiomers had 105% and 115% of lipid density relative to racemic DOTAP, respectively. These findings suggest an important role of lipid chirality in future development of lipid based siRNA delivery systems.
DOTAP; enantiomer; siRNA; lipoplex; aromatase; modeling
Proteus mirabilis is one of the pathogenic agents that commonly causes urinary tract infections among elderly individuals and long-term catheterized patients. Here, we report a draft genome sequence of Proteus mirabilis strain PR03 (3,932,623 bp, with a G+C content of 38.6%) isolated from a local hospital in Malaysia.
To assess the associations of race and socioeconomic status (SES) with pressure ulcers (PU) after accounting for health care access (HCA) among persons with spinal cord injury (SCI).
Large specialty hospital in the southeastern United States.
Persons with traumatic SCI who 1) had residual effects from their injury, 2) were 18 years or older at survey, and 3) were a year or more post-injury at survey (n=2,549).
Main Outcome Measures
Outcomes were measured by mail-in survey: having a current PU (yes vs. no), having a PU in the past year with or without reduced sitting time (no PU, no reduced sitting time, month or less, 5+ weeks), and having at least 1 PU surgery since SCI onset (yes vs. no).
Of participants, 39.3% reported a PU in the past year, 19.9% had a current PU, and 21.9% reported having had surgery for a PU since their SCI onset. While race was preliminarily associated with each PU outcome, it became non-significant after controlling for SES and HCA. In each analysis, household income was significantly associated with PU outcomes after controlling for demographic and injury factors and remained significant after accounting for the HCA factors. Persons with lower income had higher odds of each PU outcome. HCA was not consistently related to PU outcomes.
Even after accounting for HCA, household income, a measure of SES, remained significantly associated with PU outcomes after SCI; however, race became non-significant.
spinal cord injury; pressure ulcer; race; socioeconomic factors; health services accessibility
The polybrominated diphenyl ethers (PBDEs) constitute a class of flame retardants whose residues have markedly increased in fish and human tissues during the last decade. In particular, the levels of certain PBDE congeners in salmon have raised concern regarding potential risks associated with dietary PBDE exposures. However, little is known regarding PBDE-mediated cell injury in relevant in vitro cell models. We conducted a comparative study of oxyradical production and cell injury in rainbow trout gill (RTgill-W1) and trout liver cells (RTL-W1) exposed to 2,2′,4,4′-tetrabromodiphenyl ether (BDE 47), a predominant BDE residue found in fish tissues such as salmonids. Exposure to low micromolar concentrations of BDE 47 elicited a significant loss in RTgill-W1 and RTL-W1 cell viability as measured by alamarBlue assay. The dose-response of BDE toxicity differed among the two cell lines, with the RTL-W1 liver cells showing greater resistance to toxicity at lower BDE 47 doses, but a more dramatic loss of viability relative to gill cells when challenged with higher (50 μM) doses. The sensitivity of the trout liver cells at higher BDE 47 exposures was reflected by a higher basal production of oxygen radical production by 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence that was markedly enhanced in the presence of BDE 47, suggesting an overwhelming of trout liver cell antioxidant defense pathways. Collectively, our data indicate that RTgill-W1 and RTL-W1 liver cells are sensitive to BDE 47-mediated cell injury through a mechanism that may involve oxidative stress. Our data also provide an in vitro basis for potential tissue differences in BDE 47-mediated cell injury.
2,2′,4,4′-Tetrabromodiphenyl ether; Rainbow trout; Cell lines; Reactive oxygen species
To identify and describe the frequency of reliance on assistive devices and/or people for ambulating distances and stair climbing.
A total of 429 adults with traumatic spinal cord injury who were able to walk at least 10 m were identified through inpatient and outpatient hospital databases at a specialty hospital in the southeast United States.
Data were collected using a self-report questionnaire including items related to distances walked and devices used for ambulation.
Participants best able to ambulate community distances were those who were independent with ambulation and those who used one cane or crutch. Reliance on people or use of a walker was associated with walking shorter distances. Regression analysis indicated reliance on devices or people for walking predicted variation in ability to ambulate community distances after controlling for demographic and injury characteristics.
This study suggests that reliance on devices or a person for assistance is important to consider when assessing potential for achieving functional community ambulation.
Spinal cord injuries; Incomplete; Walking; Self-help devices; Ambulation; Assistive technology; Pain; Depression
Lack of safe and efficient delivery of siRNA remains the greatest hurdle for the therapeutic application of siRNA. This article reports synthesis and evaluation of novel lipoidal amine-based nanocarrier (LANC) formulations for siRNA delivery.
Physicochemical properties were analyzed for LANC formulations. siRNA delivery efficiency of LANC–siRNA complexes was determined using a luciferase reporter gene assay. Cytotoxicity of the LANC–siRNA complexes was measured by the MTS assay. Finally, cellular uptake and cytoplasmic release of siRNA were analyzed using flow cytometry.
The LANC formulation facilitated siRNA uptake and release into the cytoplasm, mediating significant luciferase knockdown (70% inhibition).
MicroRNA-29b (miR-29b) expression has been shown to be reduced in non-small–cell lung cancer (NSCLC) tissues. Here, we have identified the oncogene cyclin-dependent protein kinase 6 (CDK6) as a direct target of miR-29b in lung cancer. We hypothesized that in vivo restoration of miR-29b and thus targeting of genes important to tumor initiation and progression may represent an option for lung cancer treatment. We developed a cationic lipoplexes (LPs)-based carrier that efficiently delivered miR-29b both in vitro and in vivo. LPs containing miR-29b (LP-miR-29b) efficiently delivered miR-29b to NSCLC A549 cells, reduced the expression of key targets CDK6, DNMT3B, and myeloid cell leukemia sequence 1 (MCL1), as well as cell growth and clonogenicity of A549 cells. In addition, the IC50 for cisplatin in the miR-29b–treated cells was effectively reduced. In a xenograft murine model, LPs efficiently accumulated at tumor sites. Systemic delivery of LP-miR-29b increased the tumor miR-29b expression by approximately fivefold, downregulated the tumor mRNA expression of CDK6, DNMT3B, and MCL1 by ~57.4, ~40.5, and ~52.4%, respectively, and significantly inhibited tumor growth by ~60% compared with LP-miR-NC (negative control). Our results demonstrate that cationic LPs represent an efficient delivery system that holds great potential in the development of miRNA-based therapeutics for lung cancer treatment.
cationic lipoplexes; lung cancer; microRNA
Antisense oligonucleotide G3139-mediated down-regulation of Bcl-2 is a potential strategy for overcoming chemoresistance in leukemia. However, the limited efficacy shown in recent clinical trials calls attention to the need for further development of novel and more efficient delivery systems. In order to address this issue, transferrin receptor (TfR)-targeted, protamine-containing lipid nanoparticles (Tf-LNs) were synthesized as delivery vehicles for G3139. The LNs were produced by an ethanol dilution method and lipid-conjugated Tf ligand was then incorporated by a post-insertion method. The resulting Tf-LNs had a mean particle diameter of ~ 90 nm and G3139 loading efficiency of 90.4%. Antisense delivery efficiency of Tf-LNs was evaluated in K562, MV4-11 and Raji leukemia cell lines. The results showed that Tf-LNs were more effective than non-targeted LNs and free G3139 (p <0.05) in decreasing Bcl-2 expression (by up to 62% at the mRNA level in K562 cells) and in inducing caspase-dependent apoptosis. In addition, Bcl-2 down-regulation and apoptosis induced by Tf-LN G3139 were shown to be blocked by excess free Tf and thus were TfR-dependent. Cell lines with higher TfR expression also showed greater Bcl-2 down-regulation. Furthermore, upregulation of TfR expression in leukemia cells by iron chelator deferoxamine resulted in a further increase in antisense effect (up to 79% Bcl-2 reduction in K562 at the mRNA level) and in caspase-dependent apoptosis (by ~ 3-fold) by Tf-LN. Tf-LN mediated delivery combined with TfR up-regulation by deferoxamine appears to be a potentially promising strategy for enhancing the delivery efficiency and therapeutic efficacy of antisense oligonucleotides.
Transferrin receptor; lipid nanoparticles; protamine; antisense; oligonucleotide; G3139
Antisense oligonucleotide G3139 is designed for Bcl-2 downregulation and is known to induce toll-like receptor activation. Novel stabilized lipid-polycation-DNA (sLPD) nanoparticles were constructed and evaluated for the delivery of G3139 to human carcinoma KB cells and for bioactivity in vivo. Polyethylenimine (PEI) was incorporated as a DNA condensing agent. The lipid composition used was DOTAP/DDAB/Chol/TPGS/linoleic acid/hexadecenal at molar ratios of 30/30/34/1/5/0.2. The nanoparticles were stabilized by the formation of a reversible covalent bond between the aldehyde group on the cis-11-hexadecenal and amines on the PEI. When sLPDs were used to transfect KB cells, 90.4% Bcl-2 downregulation was observed, compared to no significant down-regulation by free G3139 and 54.6% down regulation by non-stabilized LPD-G3139. The sLPDs were then evaluated for therapeutic efficacy in mice bearing KB subcutaneous tumors and were found to trigger a strong antitumor response, inhibiting tumor growth and prolonging survival with 72% increase in lifespan (ILS). Consistent with previous reports on other G3139 nanoparticles, the increased anti-tumor activities of sLPDs in vivo were found to be associated with increased cytokine induction rather than Bcl-2 down-regulation, suggesting an immunological mechanism.
Nanoparticles; antisense oligonucleotide; reversible crosslinking; cancer; immunotherapy; drug delivery
Non-ionic surfactant vesicles, or SPANosomes (SPs), comprised of cationic lipid and sorbitan monooleate (Span 80) were synthesized and evaluated as siRNA vectors. The SPs had a mean diameter of less than 100 nm and exhibited excellent colloidal stability. The SP/siRNA complexes possessed a slightly positive zeta potential of 12 mV and demonstrated a high siRNA incorporation efficiency of greater than 80%. Cryogenic transmission electron microscopy (cryo-TEM) imaging of the SP/siRNA indicated a predominantly core-shell structure. The SP/siRNA complexes were shown to efficiently and specifically silence expression of both green fluorescent protein (GFP) (66% knockdown) and aromatase (77% knockdown) genes in breast cancer cell lines. In addition, the cellular trafficking pathway of the SP/siRNA was investigated by confocal microscopy using molecular beacons as probes for cytosolic delivery. The results showed efficient endosomal escape and cytosolic delivery of the siRNA cargo following internalization of the SP/siRNA complexes. In conclusion, Span 80 is a potent helper lipid and the SPs are promising vehicles for siRNA delivery.
Drug delivery; Nanoparticles; Surfactant vesicles; siRNA; Molecular beacon
To evaluate the association of demographic, behavioral, and socioeconomic factors with all-cause mortality while controlling for health status among a cohort of participants with severe disability related to spinal cord injury (SCI).
Prospective cohort study.
Data were analyzed at a major medical university in the Southeast United States of America.
Participants included 1361 adults with traumatic SCI of at least one year duration who were recruited through a large specialty hospital in the Southeast United States of America. Three Cox proportional hazards models were generated relating the predictors to all-cause mortality.
Age, disability, smoking, and income were significant in the final model. Both current (hazard ratio [HR]=2.03, 95% confidence interval [CI]=1.46–2.82) and former smokers (HR=1.58, CI=1.16–2.16) were at elevated hazard of mortality, as were those with incomes under $10,000 (HR=2.29, CI=1.53–3.44) and between $10,000–$35,000 (HR=1.47, CI=1.03–2.10).
Even after controlling for health and severity of disability, the coefficients for smoking and income were significant, exceeding that reported previously within the general population. The importance of these factors may be magnified after severe disability, even though life expectancy is already greatly diminished in this population.
spinal cord injuries; socioeconomic factors; behavior; mortality; life expectancy; health status
To examine behavioral risk factors in relation to fatigue after spinal cord injury (SCI), specifically cardiovascular related behaviors, prescription medication use, and alcohol and cigarette use.
A medical university in the Southeastern United States.
2296 adults at least one year post-SCI from a large specialty hospital in the Southeast responded to a mail-in survey.
Main Outcomes Measure
The Modified Fatigue Impact Scale-5 item version was used to assess disabling fatigue.
Of participants, 8.3% had disabling fatigue, 45.3% reported fatigue rarely to never impacted their life, and 46.4% reported having some fatigue. Persons who reported having less exercise than others with a similar injury level were 2.49 times as likely to have disabling fatigue as persons who reported more exercise. Those with a fair or poor diet were also more likely to have disabling fatigue. Use of prescription medication to treat pain was associated with disabling fatigue, as was being CAGE positive. Among non-behavioral variables, race and injury severity were significantly associated with disabling fatigue.
We identified several behavioral predictors of disabling fatigue, including cardiovascular risk factors, prescription medication use, and alcohol use. These factors are important as they are able to be modified and could be potential factors for prevention or intervention.
spinal cord injury; fatigue; behavior