Citations

Object The clinical success rates of anterior cervical discectomy and fusion (ACDF) procedures are substantially reduced as more cervical levels are included in the fusion procedure. One method that has been proposed as an adjunctive technique for multilevel ACDF is the placement of screws across the facet joints (“transfacet screws”). However, the biomechanical stability imparted by transfacet screw placement (either unilaterally or bilaterally) has not been reported. Therefore, the purpose of this study was to determine the acute stability conferred by implementation of unilateral and bilateral transfacet screws to an ACDF construct. Methods Eight C2–T1 fresh-frozen human cadaveric spines (3 female and 5 male; mean age 50 years) were tested. Three different instrumentation variants were performed on cadaveric cervical spines across C4–7: 1) ACDF with an intervertebral spacer and standard plate/screw instrumentation; 2) ACDF with an intervertebral spacer and standard plate/screw instrumentation with unilateral facet screw placement; and 3) ACDF with an intervertebral spacer and standard plate/screw instrumentation with bilateral facet screw placement. Kinetic ranges of motion in flexion-extension, lateral bending, and axial rotation at 1.5 Nm were captured after each of these procedures and were statistically analyzed for significance. Results All 3 fixation scenarios produced statistically significant reductions (p < 0.05) in all 3 bending planes compared with the intact condition. The addition of a unilateral facet screw to the ACDF construct produced significant reductions at the C4–5 and C6–7 levels in lateral bending and axial rotation but not in flexion-extension motion. Bilateral facet screw fixation did not produce any statistically significant decreases in flexion-extension motion compared with unilateral facet screw fixation. However, in lateral bending, significant reductions at the C4–5 and C5–6 levels were observed with the addition of a second facet screw. The untreated, adjacent levels (C2–3, C3–4, and C7–1) did not demonstrate significant differences in range of motion. Conclusions The data demonstrated that adjunctive unilateral facet screw fixation to an ACDF construct provides significant gains in stability and should be considered a potential option for increasing the likelihood for obtaining a successful arthrodesis for multilevel ACDF procedures.

The ionic liquid N‐ethyl‐N′‐methyl imidazolium chloride (EMIMCl) has been described as being very efficient in promoting refolding of the recombinant plasminogen activator rPA. Our study reveals that molar concentrations of EMIMCl increase the solubility of native and unfolded proteins due to favorable interactions with amino acid side chains rather than favorably interacting with the peptide backbone. This delicate balance of favorable interactions with side chains and unfavorable interactions with the peptide backbone provides a molecular explanation of how EMIMCl suppresses protein aggregation and simultaneously promotes refolding. By contrast, high concentrations of EMIMCl denature proteins because of a reduced water content and strong favorable interactions with amino acid side chains. This denatured species is not soluble and aggregates because, in contrast to the classical denaturants, guanidine hydrochloride and urea, EMIMCl does not solubilize the peptide backbone.Structured digital abstract PNP and PNP bind by molecular sieving (1, 2, 3, 4)

Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.

Background— Regenerative cell-based therapies are associated with limited myocardial retention of delivered stem cells. The objective of this study is to develop an endocardial delivery system for enhanced cell retention. Methods and Results— Stem cell retention was simulated in silico using 1- and 3-dimensional models of tissue distortion and compliance associated with delivery. Needle designs, predicted to be optimal, were accordingly engineered using nitinol, a nickel and titanium alloy displaying shape memory and superelasticity. Biocompatibility was tested with human mesenchymal stem cells. Experimental validation was performed with species-matched cells directly delivered into Langendorff-perfused porcine hearts or administered percutaneously into the endocardium of infarcted pigs. Cell retention was quantified by flow cytometry and real-time quantitative polymerase chain reaction methodology. Models, computing optimal distribution of distortion calibrated to favor tissue compliance, predicted that a 75°-curved needle featuring small-to-large graded side holes would ensure the highest cell retention profile. In isolated hearts, the nitinol curved needle catheter (C-Cath) design ensured 3-fold superior stem cell retention compared with a standard needle. In the setting of chronic infarction, percutaneous delivery of stem cells with C-Cath yielded a 37.7±7.1% versus 10.0±2.8% retention achieved with a traditional needle without effect on biocompatibility or safety. Conclusions— Modeling-guided development of a nitinol-based curved needle delivery system with incremental side holes achieved enhanced myocardial stem cell retention.

ABSTRACT Measles virus (MV) lacking expression of C protein (C KO ) is a potent activator of the double-stranded RNA (dsRNA)-dependent protein kinase (PKR), whereas the isogenic parental virus expressing C protein is not. Here, we demonstrate that significant amounts of dsRNA accumulate during C KO mutant infection but not following parental virus infection. dsRNA accumulated during late stages of infection and localized with virus replication sites containing N and P proteins. PKR autophosphorylation and stress granule formation correlated with the timing of dsRNA appearance. Phospho-PKR localized to dsRNA-containing structures as revealed by immunofluorescence. Production of dsRNA was sensitive to cycloheximide but resistant to actinomycin D, suggesting that dsRNA is a viral product. Quantitative PCR (qPCR) analyses revealed reduced viral RNA synthesis and a steepened transcription gradient in C KO virus-infected cells compared to those in parental virus-infected cells. The observed alterations were further reflected in lower viral protein expression levels and reduced C KO virus infectious yield. RNA deep sequencing confirmed the viral RNA expression profile differences seen by qPCR between C KO mutant and parental viruses. After one subsequent passage of the C KO virus, defective interfering RNA (DI-RNA) with a duplex structure was obtained that was not seen with the parental virus. We conclude that in the absence of C protein, the amount of PKR activator RNA, including DI-RNA, is increased, thereby triggering innate immune responses leading to impaired MV growth.