Kyphoscoliosis and hiatal hernia: anatomical analysis stimulates new clinical interest

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Characterization of kyphoscoliosis and associated giant hiatal hernia in a 97-year-old female cadaver

The purpose of this investigation was to characterize severe kyphosis and scoliosis (kyphoscoliosis) and giant hiatal hernia (HH) in a 97-year-old female cadaver. Kyphosis is a ventral curvature of the thoracic spine that exceeds 50°. Scoliosis (lateral spinal curvature) is usually combined with vertebral rotation. HH is a hernia in which part of the gastrointestinal (GI) tract protrudes through the esophageal opening of the diaphragm. Although kyphoscoliosis has been suggested as a causative factor in the development of HH, scarce published data exist. If true, then this is clinically important in the evaluation and treatment of patients that present with spinal deformities and GI symptoms. Gross anatomical dissection was done. Vertebral deformities and displacement of structures were visualized with digital radiologic imaging using full-body x-ray films, and high-resolution CT and MRI Scans. Image analysis, multi-planar reformatting, and 3D- reconstruction were done on radiographic series. The Cobb and Aaro-Dahlborn Methods were used to determine the degree of spinal curvature and vertebral rotation, respectively. To examine the possible relationship between kyphoscoliosis and HH, intra-abdominal volume (IAV) was measured and compared to the IAV of unaffected cadavers. The heart was displaced superior and to the left with the apex touching the thoracic cage, whereas the aorta was 7.3 cm to the right of midline. The stomach was completely within the mediastinum. Thoracic dextroscoliosis, lumbar levoscoliosis and thoracic kyphosis had Cobb Angles of 45°, 34° and 78°, respectively. All thoracic and lumbar vertebrae were left-rotated; maximum rotations were T12 (18°) and L5 (29°). IAV was 4224 cm3, and that of unaffected females ranged from 4449 to 7927 cm3. This study provides insight into the relationship between kyphoscoliosis and HH. We suggest that reduced IAV caused by kyphoscoliosis may contribute to the development and progression of paraesophageal hernias in patients with laxity of the diaphragmatic hiatal musculature

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Effect of pendant group on pDNA delivery by cationic-ß-cyclodextrin:alkyl-PVA-PEG pendant polymer complexes.

We have previously shown that cationic-ß-cyclodextrin:R-poly(vinyl alcohol)-poly(ethylene glycol) (CD+:R-PVA-PEG) pendant polymer host:guest complexes are safe and efficient vehicles for nucleic acid delivery, where R = benzylidene-linked adamantyl or cholesteryl esters. Herein, we report the synthesis and biological performance of a family of PVA-PEG pendant polymers whose pendant groups have a wide range of different affinities for the ß-CD cavity. Cytotoxicity studies revealed that all of the cationic-ß-CD:pendant polymer host:guest complexes have 100-1000-fold lower toxicity than branched polyethylenimine (bPEI), with pDNA transfection efficiencies that are comparable to bPEI and Lipofectamine 2000. Complexes formed with pDNA at N/P ratios greater than 5 produced particles with diameters in the 100-170 nm range and ζ-potentials of 15-35 mV. Gel shift and heparin challenge experiments showed that the complexes are most stable at N/P ≥ 10, with adamantyl- and noradamantyl-modified complexes displaying the best resistance toward heparin-induced decomplexation. Disassembly rates of fluoresceinated-pDNA:CD(+):R-PVA-PEG-rhodamine complexes within HeLa cells showed a modest dependence on host:guest binding constant, with adamantyl-, noradamantyl-, and dodecyl-based complexes showing the highest loss in FRET efficiency 9 h after cellular exposure. These findings suggest that the host:guest binding constant has a significant impact on the colloidal stability in the presence of serum and cellular uptake efficiency, whereas endosomal disassembly and transfection performance of cationic-ß-CD:R-poly(vinyl alcohol)-poly(ethylene glycol) pendant polymer complexes appears to be controlled by the hydrolysis rates of the acetal grafts onto the PVA main chain.

Microfluidic Assembly of Cationic-ß-Cyclodextrin:Hyaluronic Acid-Adamantane Host:Guest pDNA Nanoparticles.

Traditionally, transfection complexes are typically formed by bulk mixing, producing particles with high polydispersity and limited control over vector size. Herein, we demonstrate the use of a commercial micro-reactor to assemble pDNA:cationic cyclodextrin:pendant polymer nanoparticles using a layer-by-layer approach. Our studies reveal that the particles formulated via microfluidic assembly have much smaller sizes, lower polydispersity, lower ζ-potentials, and comparable cell viability and transfection profiles in HeLa cells than bulk mixed particles. The complexes also show a flow rate-dependent stability, with particles formed at slower flow rates giving rise to more stable complexes as determined by heparin challenge. Our findings suggest that microfluidic reactors offer an attractive method for assembling reproducible, size-controlled complexes from multi-component transfection complex assemblies.

Multi-armed cationic cyclodextrin:poly(ethylene glycol) polyrotaxanes as efficient gene silencing vectors.

A family of branched polyrotaxanes (bPRTx(+)), threaded with multiple cationic α-cyclodextrins (α-CDs) onto a multi-armed poly(ethylene glycol) (PEG) core, were synthesized and studied as gene silencing vectors. These bPRTx(+) formed stable, positively charged complexes with diameters of 150-250 nm at N/P ratios as low as 2.5. The bPRTx(+) materials were shown to have gene-silencing efficiencies comparable to those of Lipofectamine 2000 (L2k) and bPEI, while displaying similar toxicity profiles. The unique structure of these polyrotaxanes allows them to effectively condense and complex siRNA into nanoparticles at much lower N/P ratios than L2k or bPEI. These findings suggest that bPRTx(+) may be useful materials for gene therapy applications.