Quantitative analysis of the nonlinear displacement-load behavior of the lumbar spine.

There is currently no universal model or fitting method to characterize the visco-elastic behavior of the lumbar spine observed in displacement versus load hysteresis loops. In this study, proposed methods for fitting these loops, along with the metrics obtained, were thoroughly analyzed. A spline fitting technique was shown to provide a consistent approximation of spinal kinetic behavior that can be differentiated and integrated. Using this tool, previously established metrics were analyzed using data from two separate studies evaluating different motion preservation technologies. Many of the metrics, however, provided no significant differences beyond range of motion analysis. Particular attention was paid to how different definitions of the neutral zone capture the high-flexibility region often seen in lumbar hysteresis loops. As a result, the maximum slope was introduced and shown to be well defined. This new parameter offers promise as a descriptive measurement of spinal instability in vitro and may have future implications in clinical diagnosis and treatment of spinal instability. In particular, it could help in assigning treatments to specific stabilizing effects in the lumbar spine.

Development of a model based method for investigating facet articulation.

Reported investigations of facet articulation in the human spine have often been conducted through the insertion of pressure sensitive film into the joint space, which requires incision of the facet capsule and may alter the characteristics of interaction between the facet surfaces. Load transmission through the facet has also been measured using strain gauges bonded to the articular processes. While this method allows for preservation of the facet capsule, it requires extensive instrumentation of the spine, as well as strain-gauge calibration, and is highly sensitive to placement and location of the strain gauges. The inherently invasive nature of these techniques makes it difficult to translate them into medical practice. A method has been developed to investigate facet articulation through the application of test kinematics to a specimen-specific rigid-body model of each vertebra within a lumbar spine segment. Rigid-body models of each vertebral body were developed from CT scans of each specimen. The distances between nearest-neighboring points on each facet surface were calculated for specific time frames of each specimen's flexion/extension test. A metric describing the proportion of each facet surface within a distance (2 mm) from the neighboring surface, the contact area ratio (CAR), was calculated at each of these time frames. A statistically significant difference (p<0.037) was found in the CAR between the time frames corresponding to full flexion and full extension in every level of the lumbar spine (L1-L5) using the data obtained from the seven specimens evaluated in this study. The finding that the contact area of the facet is greater in extension than flexion corresponds to other findings in the literature, as well as the generally accepted role of the facets in extension. Thus, a biomechanical method with a sufficiently sensitive metric is presented as a means to evaluate differences in facet articulation between intact and treated or between healthy and pathologic spines.

Molecular natural history of breast cancer: Leveraging transcriptomics to predict breast cancer progression and aggressiveness.

BACKGROUND: Characterizing breast cancer progression and aggressiveness relies on categorical descriptions of tumor stage and grade. Interpreting these categorical descriptions is challenging because stage convolutes the size and spread of the tumor and no consensus exists to define high/low grade tumors. METHODS: We address this challenge of heterogeneity in patient-specific cancer samples by adapting and applying several tools originally created for understanding heterogeneity and phenotype development in single cells (specifically, single-cell topological data analysis and Wanderlust) to create a continuous metric describing breast cancer progression using bulk RNA-seq samples from individual patient tumors. We also created a linear regression-based method to predict tumor aggressiveness in vivo from bulk RNA-seq data. RESULTS: We found that breast cancer proceeds along three convergent phenotype trajectories: luminal, HER2-enriched, and basal-like. Furthermore, 31 296 genes (for luminal cancers), 17 827 genes (for HER2-enriched), and 18 505 genes (for basal-like) are dynamically differentially expressed during breast cancer progression. Across progression trajectories, our results show that expression of genes related to ADP-ribosylation decreased as tumors progressed (while PARP1 and PARP2 increased or remained stable), suggesting the potential for a differential response to PARP inhibitors based on cancer progression. Additionally, we developed a 132-gene expression regression equation to predict mitotic index and a 23-gene expression regression equation to predict growth rate from a single breast cancer biopsy. CONCLUSION: Our results suggest that breast cancer dynamically changes during disease progression, and growth rate of the cancer cells is associated with distinct transcriptional profiles.

Porous titanium-coated polyetheretherketone implants exhibit an improved bone-implant interface: an in vitro and in vivo biochemical, biomechanical, and histological study.

PURPOSE: Spinal interbody fusion cages are designed to provide immediate stabilization for adjoining vertebrae and ideally enable bony ingrowth to achieve successful integration. For such an implant, cells must be able to attach, move, grow, and differentiate on its surface. These cellular interactions are dependent on how the implant surface enables the coating and binding of blood and tissue fluid proteins that support cell adhesion. The purpose of this study was to evaluate the in vitro and in vivo osteoblast cell-implant surface interactions that result in osseointegration onto a surface composed of plasma-sprayed titanium on a polyetheretherketone (PEEK) substrate or titanium-coated PEEK (Ti-PEEK) (PlasmaporeXP®) as compared to uncoated PEEK implants. MATERIALS AND METHODS: The influence of the Ti-PEEK surface modification on the biochemical, biomechanical, and histological properties at the bone-implant interface is demonstrated both in vitro using simulated bone-forming cell culture experiments and in vivo using a 12- and 24-week ovine implant model. RESULTS: Osteoblast-like cells attached to the Ti-PEEK surface upregulated early bone-forming activity as measured by an increase in transcription and translation of ALP and BMP-2 when compared to cells on PEEK. Similarly, a significant increase in new bone formation, bony apposition, and pullout strength was demonstrated on Ti-PEEK implants when compared to PEEK implants at 12 and 24 weeks in an ovine implant in vivo model. CONCLUSION: The study shows that the Ti-PEEK surface demonstrated enhanced osseointegrative properties compared to PEEK both in vitro and in vivo.

Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs.

BACKGROUND: We report the 5-year outcomes from a randomized prospective trial in primary adult renal allograft recipients, designed to evaluate calcineurin inhibitor (CNI)-free immunosuppression on kidney transplant function. METHODS: Sixty-one patients were randomized to either sirolimus (n=31) or cyclosporine (n=30) after basiliximab induction and mycophenolate mofetil (MMF) with steroids. Sirolimus was concentration controlled at 10-12 ng/mL for at least 6 months. RESULTS: After 5 years, sirolimus-MMF-steroids compared to cyclosporine-MMF-steroids provides similar patient survival (87.1 vs. 90%, P=0.681), acute rejection rates (12.9 vs. 23.3%, P=0.22), total cholesterol (209.1 vs. 204.3 mg/dL, P=0.973), urine protein/creatinine ratios (0.398 vs. 0.478 mg/dL, P=0.72), and overall medical and surgical morbidity (P=NS). Although unadjusted patient survival was similar, sirolimus based CNI-free patients had longer death censored graft survival (96.4 vs. 76.7%, P=0.0265), higher glomerular filtration rate (GFR) by the abbreviated Modified Diet in Renal Disease (66.7 vs. 50.7 cc/min, P=0.0075), and fewer graft losses from chronic allograft nephropathy. The Banff chronic scores at two years were strong predictors of 5-year GFR. At 5 years, there were six de novo (three solid organ, three skin) cancers in the CNI group and only two de novo (one skin, one leukemia, no solid organ) cancers in the sirolimus group (P=NS). CONCLUSIONS: This study of low to moderate risk patients demonstrates that excellent 5-year kidney transplant outcomes can be achieved without CNI drugs, when therapeutic drug monitoring of sirolimus is employed. The application of CNI drug avoidance protocols to high-risk recipients (retransplants, highly sensitized, etc.), extrarenal allograft recipients, or alternative drug regimens such as steroid or MMF elimination should be subjected to controlled trials.

Genome-scale metabolic models applied to human health and disease.

Advances in genome sequencing, high throughput measurement of gene and protein expression levels, data accessibility, and computational power have allowed genome-scale metabolic models (GEMs) to become a useful tool for understanding metabolic alterations associated with many different diseases. Despite the proven utility of GEMs, researchers confront multiple challenges in the use of GEMs, their application to human health and disease, and their construction and simulation in an organ-specific and disease-specific manner. Several approaches that researchers are taking to address these challenges include using proteomic and transcriptomic-informed methods to build GEMs for individual organs, diseases, and patients and using constraints on model behavior during simulation to match observed metabolic fluxes. We review the challenges facing researchers in the use of GEMs, review the approaches used to address these challenges, and describe advances that are on the horizon and could lead to a better understanding of human metabolism. WIREs Syst Biol Med 2017, 9:e1393. doi: 10.1002/wsbm.1393 For further resources related to this article, please visit the WIREs website.

Disc nucleus fortification for lumbar degenerative disc disease: a biomechanical study.

OBJECTIVE Spinal stability is attributed in part to osteoligamentous structures, including the vertebral body, facets, intervertebral discs, and posterior elements. The materials in this study provide an opportunity to augment the degenerated nucleus without removing native disc material, a procedure introduced here as "fortification." The objective of this study was to determine the effect of nucleus fortification on lumbar disc biomechanics. METHODS The authors performed in vitro analysis of human cadaveric functional spinal units (FSUs), along with characterization and quantification of movement of the units using biomechanical data in intact, disc-only, and fortified specimens. The units underwent removal of all posterior elements and annulus and were fortified by injecting a biogel into the nucleus pulposus. Each specimen was subjected to load testing, range of motion (ROM) quantification, and disc bulge measurements. Optoelectric tracking was used to quantify disc bulge. These criteria were assessed in the intact, disc-only, and fortified treatments. RESULTS Disc-only FSUs resulted in increased ROM when compared with intact and fortified conditions. Fortification of the FSU resulted in partial restoration of normal ROM in the treatment groups. Analysis of hysteresis loops showed more linear response in the fortified groups when compared with the intact and disc-only groups. CONCLUSIONS Disc nucleus fortification increases linearity and decreases ROM.

Biomechanics of Posterior Dynamic Fusion Systems in the Lumbar Spine: Implications for Stabilization With Improved Arthrodesis.

STUDY DESIGN: A comparative biomechanical human cadaveric spine study of a dynamic fusion rod and a traditional titanium rod. OBJECTIVE: The purpose of this study was to measure and compare the biomechanical metrics associated with a dynamic fusion device, Isobar TTL Evolution, and a rigid rod. SUMMARY OF BACKGROUND DATA: Dynamic fusion rods may enhance arthrodesis compared with a rigid rod. Wolff's law implies that bone remodeling and growth may be enhanced through anterior column loading (AL). This is important for dynamic fusion rods because their purpose is to increase AL. METHODS: Six fresh-frozen lumbar cadaveric specimens were used. Each untreated specimen (Intact) underwent biomechanical testing. Next, each specimen had a unilateral transforaminal lumbar interbody fusion performed at L3-L4 using a cage with an integrated load cell. Pedicle screws were also placed at this time. Subsequently, the Isobar was implanted and tested, and finally, a rigid rod replaced the Isobar in the same pedicle screw arrangement. RESULTS: In terms of range of motion, the Isobar performed comparably to the rigid rod and there was no statistical difference found between Isobar and rigid rod. There was a significant difference between the intact and rigid rod and also between intact and Isobar conditions in flexion extension. For interpedicular displacement, there was a significant increase in flexion extension (P=0.017) for the Isobar compared with the rigid rod. Isobar showed increased AL under axial compression compared with the rigid rod (P=0.024). CONCLUSIONS: Isobar provided comparable stabilization to a rigid rod when using range of motion as the metric, however, AL was increased because of the greater interpedicular displacement of dynamic rod compared with a rigid rod. By increasing interpedicular displacement and AL, it potentially brings clinical benefit to procedures relying on arthrodesis.

Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient.

BACKGROUND: Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy. METHODS AND RESULTS: We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (P=0.016) increased mRNA expression of MMP-2 and 1.7-fold (P=0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P=0.01; 95% CI, 1.24 to 4.69). CONCLUSIONS: This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.

Patterns of myocardial endothelin-1 expression and outcome after cardiac transplantation.

BACKGROUND: Endothelin-1 (ET-1), a potent vasoconstrictor, is released in response to several inflammatory cytokines after heart transplantation. The present study correlated patterns of myocardial ET-1 expression in heart biopsies with acute rejection, post-transplantation ischemic injury, and subsequent development of coronary vasculopathy. METHODS AND RESULTS: Patterns of myocardial ET-1 expression were evaluated in 47 heart transplant recipients at 3 months after transplant. Transplant vasculopathy was documented by coronary angiography at 2 years after transplant. Expression of ET-1 was tabulated for both blood vessels and the interstitium. Vascular ET-1 expression was positive in 7/17 (41%) of patients with greater than grade 2 (International Society Heart Lung Transplant) rejection compared with 3/30 (10%) of patients with grade 0 and grade 1A rejection (P=0.02). Compared with patients with negative interstitial ET-1 expression (n=22), patients with positive interstitial ET-1 expression (n=25) had higher incidence of post-transplantation ischemic injury (52% versus 9%, P=0.002), lower mean episodes of acute rejection (> or = grade 2) during the first 3 months of transplant (1.09+/-0.66 versus 1.86+/-1.6, P=0.048), and more common vasculopathy at 2 years (50% versus 15%, P=0.02), and they tended to have worse survival (83.2% versus 100%, P=0.058). CONCLUSIONS: Vascular ET-1 expression is likely to be associated with acute rejection. Interstitial ET-1 expression, however, is more likely to be associated with post-transplantation ischemic injury and subsequent development of coronary vasculopathy.

Angiotensin II receptors from peritransplantation through first-year post-transplantation and the risk of transplant coronary artery disease.

OBJECTIVES: We evaluated whether the angiotensin II (Ang II) receptors from perioperation through one-year post-transplantation predict the transplant coronary artery disease (TCAD) progression. BACKGROUND: The role of Ang II receptors (type 1: AT(1)R; type 2: AT(2)R) in TCAD is uncertain. METHODS: We investigated 28 heart donors and the corresponding recipients. The levels of AT(1)R and AT(2)R messenger ribonucleic acid (mRNA) were examined in lymphocytes from the donor spleen and in the donor heart at one-week and one-year posttransplantation to determine their association with the progression of TCAD, measured as changes in maximal intimal thickness (CMIT) and plaque volume (CPV) by intravascular ultrasound (IVUS) examinations. RESULTS: The AT(1)R mRNA in lymphocytes from the donor spleen (CMIT: r = 0.73, p < 0.0001; CPV: r = 0.69, p < 0.0001) and in the donor hearts at one-week (CMIT: r = 0.52, p = 0.005; CPV: r = 0.56, p = 0.002) and at one-year (CMIT: r = 0.63, p < 0.0001; CPV: r = 0.43, p = 0.004) post-transplantation along with AT(2)R mRNA in the donor hearts at one-year post-transplantation (CMIT: r = 0.3, p < 0.0001; CPV: r = 0.53, p = 0.009) were univariate predictors, whereas AT(1)R mRNA in lymphocytes and in the donor hearts at one-year post-transplantation proved to be multivariate predictors of the progression of TCAD. CONCLUSIONS: These data suggest a role for Ang II receptors in the pathogenesis of TCAD and support a novel concept that TCAD may have its origin in the donor per se and may be modulated by the recipient's inherent biological factors.

Myocardial ischemic-fibrotic injury after human heart transplantation is associated with increased progression of vasculopathy, decreased cellular rejection and poor long-term outcome.

OBJECTIVES: We sought to assess the influence of peritransplant ischemia and fibrosis on the development of allograft vasculopathy, acute cellular rejection and long-term outcome. BACKGROUND: Allograft vasculopathy is a common long-term complication of cardiac transplantation. One of the potential risk factors is peritransplant allograft ischemia. METHODS: One hundred forty heart transplant recipients had baseline and one-year intravascular ultrasound analysis done to assess the progression of allograft vasculopathy. Serial endomyocardial biopsies were evaluated for cellular rejection, vascular rejection, ischemia and fibrosis. Based on histology, patients were classified into one of the following groups: nonischemic (n = 32), ischemia (n = 24), fibrosis (n = 62) or vascular rejection (n = 22). Three-color flow cytometry crossmatching (FCXM) was used to assess donor-specific human lymphocyte antigens (HLA) sensitization. Long-term outcome of patients in each group was assessed by estimating incidence of graft failure or deaths over a seven-year follow up. RESULTS: Patients in the fibrosis group had the lowest incidence of donor-specific HLA sensitization (40%, p = 0.008) and lowest average episodes of cellular rejection (1.7 +/- 1.4, p = 0.04), but they had increased coronary vasculopathy progression (change in coronary intimal thickness = 0.59 +/- 0.28 mm, p < 0.0001) and poor seven-year event-free survival (49%, p = 0.01). CONCLUSIONS: The development of fibrosis after cardiac transplantation is associated with advanced coronary vasculopathy, although a low incidence of acute cellular rejection is noted, suggesting the presence of nonimmune mechanisms in mediating the pathogenesis of allograft vasculopathy.

Laparoscopic donor nephrectomy gene expression profiling reveals upregulation of stress and ischemia associated genes compared to control kidneys.

We compared gene expression profiles from six donor kidneys prior to surgical manipulation to six kidneys removed after laparoscopic donor nephrectomy (LDN) and several hours of CO2 pneumoperitoneum. Biopsies were obtained from renal cortex and hybridized to Affymetrix HG-U133A GeneChips. For control kidneys, we identified 1380 genes present on all six samples that had a signal intensity >1,000. Functional classification of these revealed genes for cellular signaling (201; 15%), regulation of transcription (156; 11%), cellular transport (144; 10%) and cellular metabolism (111; 8%). A class comparison between the controls and LDN kidneys yielded 865 differentially expressed genes. Functional classification of the 502 genes differentially upregulated in LDN kidneys identified associations with apoptosis, cell adhesion, cell signaling, regulation of cell growth/proliferation, immune/inflammation, ischemia/stress response and proteolysis/peptidolysis. These data demonstrate an altered renal transcriptome induced by several hours of CO2 pneumoperitoneum and laparoscopic surgery characterized by upregulation of ischemia and injury associated genes.

The effect of 2-gram versus 1-gram concentration controlled mycophenolate mofetil on renal transplant outcomes using sirolimus-based calcineurin inhibitor drug-free immunosuppression.

BACKGROUND: We performed a sequential study to determine the efficacy and side effects of low-dose (1 g) mycophenolate mofetil (MMF) in a CNI drug avoidance regimen including sirolimus/steroids. METHODS: A total of 260 kidney-only recipients were given basiliximab (232) or thymoglobulin (28) induction, and sirolimus/steroids. In addition, 160 recipients were begun on standard MMF 1 g twice daily (2-g group), while 100 recipients were begun on low-dose MMF 500 mg twice daily (1-g group). The 1-g recipients were concentration controlled to keep mycophenolic acid (MPA) C0 levels at 1.8-4 microg/ml. RESULTS: There were no statistically significant differences in demographics between the groups. At 6 months there were no significant differences between the 2-g and 1-g MMF groups in patient survival (96.8% vs. 96%), graft survival (92.5% vs. 95%), biopsy-confirmed and treated acute rejection (8.8% vs. 13%), or mean creatinine mg/dL (1.41+/-0.52 vs. 1.47+/-0.67), respectively. Mean MPA C0 levels microg/ml were (4.7 vs. 2.3) at 1 month, (4.1 vs. 3.1) at 3 months, and (3.9 vs. 2.4) at 6 months. There were no significant differences at 1, 3, or 6 months in mean WBC, HgB, or platelets, or wound complications. There were significant reductions in the number of patients reporting nausea-vomiting-dyspepsia (20.6% vs. 8%, P=0.007), diarrhea (34.3% vs. 20%, P=0.01), and abdominal pains (10.6% vs. 4%, P=0.05), between the 2-g and 1-g MMF groups, respectively. CONCLUSIONS: The use of concentration-controlled 1-g MMF results in comparable transplant outcomes with less GI toxicity during the first 6 months posttransplant in a CNI drug-free sirolimus based immunosuppressive regimen.

Early and midterm risk of coronary allograft vasculopathy in patients bridged to orthotopic heart transplantation with ventricular assist devices.

BACKGROUND: Coronary transplant vasculopathy (CAV) has been associated with both immunologic and nonimmunologic factors. The impact of preoperative ventricular assist device (VAD) support on the development of CAV has not been studied. To examine this, we obtained posttransplant coronary angiograms from a group of patients bridged with VAD and compared them to post transplant coronary angiograms of a non-VAD cohort. METHODS: Adult patients undergoing orthotopic heart transplant between 1996-2000 were retrospectively studied and divided into VAD and non-VAD patients. Coronary angiograms were retrospectively reviewed and severity of coronary vasculopathy was categorized as trivial, mild, moderate, or severe. Other variables studied included recipient and donor demographics, cytotoxic panel reactive antibodies (PRA) against T-cell targets and flow cytometric crossmatching against donor T lymphocytes. RESULTS: There was no significant difference between groups regarding demographics. However, VAD patients had a sixfold greater chance of having a T-cell PRA >10% at the time of transplant (p < 0.05), and a fourfold greater chance of having a positive cross match when compared to non-VAD patients (p < 0.05). There was no significant difference in the degree of CAV between groups. Normal coronary anatomy was present in 76% of VAD patients and 64% of non-VAD patients (p = 0.37). These results were similar at 2- and 3-year follow-up (76 vs. 74% and 80 vs. 62%, respectively). CONCLUSION: Preoperative VAD use is associated with increased sensitization; however, these patients develop CAV at the same rate as those not bridged with a VAD.

Systemic activation of integrin alphaVbeta3 in donors with spontaneous intracerebral hemorrhage is associated with subsequent development of vasculopathy in the heart transplant recipient.

BACKGROUND: Recipients of hearts from donors with spontaneous intracerebral hemorrhage (ICH) are at increased risk of allograft vasculopathy compared with trauma donors. We have recently shown that the vitronectin receptor (integrin alpha(V)beta3) is upregulated in transplant vasculopathy. We hypothesized that donor ICH is associated with systemic activation of alpha(V)beta3 in the donor before transplantation. METHODS: We evaluated mRNA expressions of alpha(V)beta3 (TaqMan PCR) in endomyocardial biopsy samples at 1-week post-transplant in 20 recipients from ICH donors and 20 recipients from trauma donors. To investigate whether systemic activation of alpha(V)beta3 was present in the donor before transplantation, alpha(V)beta3 expression was also evaluated in the corresponding donor spleen lymphocytes. All patients underwent serial coronary intravascular ultrasound to evaluate for coronary vasculopathy. The baseline characteristics were similar except for increased donor age in the ICH Group. RESULTS: The ICH Group showed significant increased mRNA expression of alpha(V)beta3 in the heart biopsy samples (3.8-fold, p = 0.012) and in the corresponding donor spleen lymphocytes (3.5-fold, p = 0.014) compared with the Trauma Group. At 1 year, the ICH Group also showed increased progression of coronary vasculopathy. Multivariate regression analysis found that donor lymphocytic alpha(V)beta3 mRNA expression was independently associated with increased risk of vasculopathy (odds ratio, 1.9; 95% CI, 1.21-3.98, p = 0.03). CONCLUSIONS: Our report demonstrates the presence of systemic activation of alpha(V)beta3 in donors with spontaneous intracerebral hemorrhage and its association with the subsequent development of allograft vasculopathy in the recipient.

The effect of combined Angiotensin-converting enzyme inhibition and calcium antagonism on allograft coronary vasculopathy validated by intravascular ultrasound.

BACKGROUND: Hypertension is a potential risk factor for allograft coronary vasculopathy. We evaluated the efficacy of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists, and their combined use, on the development of coronary vasculopathy in hypertensive heart transplant recipients. METHODS: Eighty-two heart transplant recipients underwent serial intravascular ultrasound (IVUS) analysis at baseline (within 1 month) and at 1 year after transplantation and were evaluated for the development of coronary vasculopathy. Patients were divided into 4 groups. Nineteen normotensive recipients received no treatment, control (Group A). Hypertensive patients were treated with either ACE inhibitors (Group B, n = 37), calcium antagonists (Group C, n = 16), or both (Group D, n = 10). RESULTS: We found a significant reduction in IVUS indices of coronary vasculopathy in heart transplant recipients who used a combination of an ACE inhibitor and a calcium antagonist compared with recipients who used either drug alone (p < 0.05). This synergistic efficacy was independent of the baseline indices evaluated in a multivariate regression analysis model and was noted despite comparable mean arterial pressure among the 3 hypertensive groups at 1 year, thus suggesting the presence of a synergistic anti-proliferative effect beyond the anti-hypertensive efficacy. CONCLUSIONS: The combined use of an ACE inhibitor and a calcium antagonist is more effective than the individual use of either drug alone on the development of coronary vasculopathy in cardiac transplant recipients. Large randomized clinical trials are warranted to evaluate such a synergistic efficacy.

In Vitro Comparison of Dynesys, PEEK, and Titanium Constructs in the Lumbar Spine.

Introduction. Pedicle based posterior dynamic stabilization systems aim to stabilize the pathologic spine while also allowing sufficient motion to mitigate adjacent level effects. Two flexible constructs that have been proposed to act in such a manner, the Dynesys Dynamic Stabilization System and PEEK rod, have yet to be directly compared in vitro to a rigid Titanium rod. Methods. Human lumbar specimens were tested in flexion extension, lateral bending, and axial torsion to evaluate the following conditions at L4-L5: Intact, Dynesys, PEEK rod, Titanium rod, and Destabilized. Intervertebral range of motion, interpedicular travel, and interpedicular displacement metrics were evaluated from 3rd-cycle data using an optoelectric tracking system. Results. Statistically significant decreases in ROM compared to Intact and Destabilized conditions were detected for the instrumented conditions during flexion extension and lateral bending. AT ROM was significantly less than Destabilized but not the Intact condition. Similar trends were found for interpedicular displacement in all modes of loading; however, interpedicular travel trends were less consistent. More importantly, no metrics under any mode of loading revealed significant differences between Dynesys, PEEK, and Titanium. Conclusion. The results of this study support previous findings that Dynesys and PEEK constructs behave similarly to a Titanium rod in vitro.

Range of motion of the intact lumbar segment: a multivariate study of 42 lumbar spines.

BACKGROUND: A thorough understanding of the biomechanical characteristics of the healthy human spine is critical in furthering the treatment of spinal pathology. The goal of this study was to investigate the motion of the intact lumbar spine segment as measured by range of motion (ROM), and to investigate the dependencies thereof on gender and intervertebral level. MATERIALS AND METHODS: Kinematic data was obtained for 42 human lumbar segments (L1-S1) in response to a pure-moment loading protocol in flexion extension (FE), lateral bending (LB) and axial torsion (AT). Data was obtained for 204 individual functional spinal units (91 female, 113 male). Multivariate analysis of variance was conducted to detect differences between genders and intervertebral levels in each mode of loading. Correlations between ROM and donor demographics, including height, weight, and age, were conducted. RESULTS: ROM was significantly greater for females than for males in FE, LB and AT (p<0.001). ROM tended to increase down the vertebral column in FE. L3-4 FE ROM was significantly greater than L1-2 (p=0.024), and L4-5 and L5-S1 FE ROM were significantly greater than for every other level (p<0.003). LB ROM tended to be greater toward the center of the segment with L2-3, L3-4 and L4-5 ROM being significantly greater than both L1-2 (p<0.001) and L5-S1 (p=0.006, p<0.001, p=0.043, respectively). A similar trend was found for AT, however only L1-2 was significantly less than all other levels (p=0.042, p<0.001, p<0.001, and p=0.034 for L2-3, L3-4, L4-5, and L5-S1 respectively). CONCLUSION: The significant differences in lumbar ROM between male and female spine segments and between the intervertebral levels must be taken into account in study design in order to prevent biases in outcomes. The significant differences in ROM between levels may also have critical implications in the design of spinal implants, particularly those designed to maintain or restore healthy motion.

A novel, dynamic pattern-based analysis of NF-κB binding during the priming phase of liver regeneration reveals switch-like functional regulation of target genes.

Following partial hepatectomy, a coordinated series of molecular events occurs to regulate hepatocyte entry into the cell cycle to recover lost mass. In rats during the first 6 h following resection, hepatocytes are primed by a tightly controlled cytokine response to prepare hepatocytes to begin replication. Although it appears to be a critical element driving regeneration, the cytokine response to resection has not yet been fully characterized. Specifically, the role of one of the key response elements to cytokine signaling (NF-κB) remains incompletely characterized. In this study, we present a novel, genome-wide, pattern-based analysis characterizing NF-κB binding during the priming phase of liver regeneration. We interrogated the dynamic regulation of priming by NF-κB through categorizing NF-κB binding in different temporal profiles: immediate sustained response, early transient response, and delayed response to partial hepatectomy. We then identified functional regulation of NF-κB binding by relating the temporal response profile to differential gene expression. We found that NF-κB bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy. NF-κB also transiently regulates genes responsible for lipid biosynthesis and transport as well as induction of apoptosis following hepatectomy. By the end of the priming phase, NF-κB regulation of genes involved in inflammatory response, negative regulation of cell death, and extracellular structure organization became prominent. These results suggest that NF-κB regulates target genes through binding and unbinding in immediate, transient, and delayed patterns. Such dynamic switch-like patterns of NF-κB binding may govern different functional transitions that drive the onset of regeneration.