ABSTRACT
Creating the optimal environment for effective and long term osseointegration is a heavily researched and sought-after design criteria for orthopedic implants. A validated multimaterial finite element (FE) model was developed to replicate and understand the results of an experimental in vivo push-out osseointegration model. The FE model results closely predicted global force (at 0.5 mm) and stiffness for the 50-90% porous implants with an r2 of 0.97 and 0.98, respectively. In addition, the FE global force at 0.5 mm showed a correlation to the maximum experimental forces with an r2 of 0.90. The highest porosity implants (80-90%) showed lower stiffnesses and more equitable load sharing but also failed at lower a global force level than the low porosity implants (50-70%). The lower strength of the high porosity implants caused premature plastic deformation of the implant itself during loading as well as significant deformations in the ingrown and surrounding bone, resulting in lower overall osseointegration strength, consistent with experimental measurements. The lower porosity implants showed a balance of sufficient bony ingrowth to support osseointegration strength coupled with implant mechanical properties to circumvent significant implant plasticity and collapse under the loading conditions. Together, the experimental and finite element modeling results support an optimal porosity in the range of 60-70% for maximizing osseointegration with current structure and loading.
Subject(s)
Finite Element Analysis , Materials Testing , Osseointegration , Porosity , Prostheses and Implants , Mechanical Phenomena , Animals , Metals/chemistry , Stress, MechanicalABSTRACT
PURPOSE: To evaluate the biological and biomechanical effects of fenestration/microdiscectomy in an in vivo rabbit model, and in doing so, create a preclinical animal model of IVDD. METHODS: Lateral lumbar IVD fenestration was performed in vivo as single- (L3/4; n = 12) and multi-level (L2/3, L3/4, L4/5; n = 12) fenestration in skeletally mature 6-month-old New Zealand White rabbits. Radiographic, micro-CT, micro-MRI, non-destructive robotic range of motion, and histological evaluations were performed 6- and 12-weeks postoperatively. Independent t tests, one-way and two-way ANOVA and Kruskal-Wallis tests were used for parametric and nonparametric data, respectively. Statistical significance was set at P < 0.05. RESULTS: All rabbits recovered uneventfully from surgery and ambulated normally. Radiographs and micro-CT demonstrated marked reactive proliferative osseous changes and endplate sclerosis at fenestrated IVDs. Range of motion at the fenestrated disc space was significantly reduced compared to intact controls at 6- and 12-weeks postoperatively (P < 0.05). Mean disc height index percentage for fenestrated IVDs was significantly lower than adjacent, non-operated IVDs for both single and multi-level groups, at 6 and 12 weeks (P < 0.001). Pfirrmann MRI IVDD and histological grading scores were significantly higher for fenestrated IVDs compared to non-operated adjacent and age-matched control IVDs for single and multi-level groups at 6 and 12 weeks (P < 0.001). CONCLUSIONS: Fenestration, akin to microdiscectomy, demonstrated significant biological, and biomechanical effects in this in vivo rabbit model and warrants consideration by veterinary and human spine surgeons. This described model may be suitable for preclinical in vivo evaluation of therapeutic strategies for IVDD in veterinary and human patients.
Subject(s)
Disease Models, Animal , Intervertebral Disc , Lumbar Vertebrae , Animals , Rabbits , Lumbar Vertebrae/surgery , Lumbar Vertebrae/diagnostic imaging , Intervertebral Disc/surgery , Intervertebral Disc/diagnostic imaging , Intervertebral Disc Degeneration/surgery , Intervertebral Disc Degeneration/diagnostic imaging , Diskectomy/methods , Range of Motion, Articular/physiology , X-Ray Microtomography , Magnetic Resonance ImagingABSTRACT
Anterior cruciate ligament (ACL) reconstruction (ACLR) is used to treat clinical instability post ACL rupture, however, there is a high rate of incomplete return to sport and rerupture. There is increasing interest in posterior tibial slope as an intrinsic risk factor for ACLR failure and persistent instability. Zoobiquity describes the collaboration between the human and veterinary professions in order to advance the scientific understanding of both fields. Given the cranial cruciate ligament (CCL) in dogs is synonymous with the anterior cruciate ligament in humans, functioning to control internal rotation and anterior translation, but osteotomies, rather than ligament reconstruction, are the mainstay of treatment for CCL rupture, this editorial sort to gain insights into this form of treatment from the veterinary world. Level of Evidence: Level V, evidence.
Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Osteotomy , Tibia , Osteotomy/methods , Tibia/surgery , Humans , Dogs , Anterior Cruciate Ligament Injuries/surgery , Anterior Cruciate Ligament Reconstruction/methods , Animals , Anterior Cruciate Ligament/surgery , Joint Instability/surgeryABSTRACT
Bacteria readily acquire resistance to traditional antibiotics, resulting in pan-resistant strains with no available treatment. Antimicrobial resistance is a global challenge and without the development of effective antimicrobials, the foundation of modern medicine is at risk. Combination therapies such as antibiotic-antibiotic and antibiotic-adjuvant combinations are strategies used to combat antibiotic resistance. Current research focuses on antimicrobial peptidomimetics as adjuvant compounds, due to their promising activity against antibiotic-resistant bacteria. Here, for the first time we demonstrate that antibiotic-peptidomimetic combinations mitigate the development of antibiotic resistance in Staphylococcus aureus and Pseudomonas aeruginosa. When ciprofloxacin and gentamicin were passaged individually at sub-inhibitory concentrations for 10 days, the minimum inhibitory concentrations (MICs) increased up to 32-fold and 128-fold for S. aureus and P. aeruginosa, respectively. In contrast, when antibiotics were passaged in combination with peptidomimetics (Melimine, Mel4, RK758), the MICs of both antibiotics and peptidomimetics remained constant, indicating these combinations were able to mitigate the development of antibiotic-resistance. Furthermore, antibiotic-peptidomimetic combinations demonstrated synergistic activity against both Gram-positive and Gram-negative bacteria, reducing the concentration needed for bactericidal activity. This has significant potential clinical applications-including preventing the spread of antibiotic-resistant strains in hospitals and communities, reviving ineffective antibiotics, and lowering the toxicity of antimicrobial chemotherapy.
Subject(s)
Anti-Infective Agents , Peptidomimetics , Anti-Bacterial Agents/pharmacology , Ciprofloxacin/pharmacology , Peptidomimetics/pharmacology , Gentamicins/pharmacology , Staphylococcus aureus , Staphylococcus , Gram-Negative Bacteria , Gram-Positive Bacteria , Anti-Infective Agents/pharmacology , Pseudomonas aeruginosa , Bacteria , Microbial Sensitivity TestsABSTRACT
The prevention and treatment of biofilm-mediated infections remains an unmet clinical need for medical devices. With the increasing prevalence of antibiotic-resistant infections, it is important that novel approaches are developed to prevent biofilms forming on implantable medical devices. This study presents a versatile and simple polydopamine surface coating technique for medical devices, using a new class of antibiotics-antimicrobial peptidomimetics. Their unique mechanism of action primes them for activity against antibiotic-resistant bacteria and makes them suitable for covalent attachment to medical devices. This study assesses the anti-biofilm activity of peptidomimetics, characterises the surface chemistry of peptidomimetic coatings, quantifies the antibacterial activity of coated surfaces and assesses the biocompatibility of these coated materials. X-ray photoelectron spectroscopy and water contact angle measurements were used to confirm the chemical modification of coated surfaces. The antibacterial activity of surfaces was quantified for S. aureus, E. coli and P. aeruginosa, with all peptidomimetic coatings showing the complete eradication of S. aureus on surfaces and variable activity for Gram-negative bacteria. Scanning electron microscopy confirmed the membrane disruption mechanism of peptidomimetic coatings against E. coli. Furthermore, peptidomimetic surfaces did not lyse red blood cells, which suggests these surfaces may be biocompatible with biological fluids such as blood. Overall, this study provides a simple and effective antibacterial coating strategy that can be applied to biomaterials to reduce biofilm-mediated infections.
Subject(s)
Anti-Infective Agents , Peptidomimetics , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Biofilms , Coated Materials, Biocompatible/chemistry , Coated Materials, Biocompatible/pharmacology , Escherichia coli , Indoles , Peptidomimetics/pharmacology , Polymers , Pseudomonas aeruginosa , Staphylococcus aureusABSTRACT
Human activities and land-use drivers combine in complex ways to affect coral reef health and, in turn, the diversity and abundance of reef fauna. Here we examine the impacts of different marine protected area (MPA) types, and various human and habitat drivers, on resource fish functional groups (i.e., total fish, herbivore, grazer, scraper, and browser biomass) along the 180 km west coast of Hawaii Island. Across survey years from 2008 to 2018, we observed an overall decrease in total fish biomass of 45%, with similar decreases in biomass seen across most fish functional groups. MPAs that prohibited a combination of lay nets, aquarium collection, and spear fishing were most effective in maintaining and/or increasing fish biomass across all functional groups. We also found that pollution, fishing, and habitat drivers all contributed to changes in total fish biomass, where the most negative impact was nitrogen input from land-based sewage disposal. Fish biomass relationships with our study drivers depended on fish functional grouping. For surgeonfish (grazers), changes in biomass linked most strongly to changes in reef rugosity. For parrotfish (scrapers), biomass was better explained by changes in commercial catch where current commercial fishing levels are negatively affecting scraper populations. Our observations suggest that regional management of multiple factors, including habitat, pollution, and fisheries, will benefit resource fish biomass off Hawaii Island.
Subject(s)
Conservation of Natural Resources , Coral Reefs , Animals , Biomass , Ecosystem , Fisheries , Fishes , Hawaii , HumansABSTRACT
PURPOSE: The objective of this study was to compare patellar height and patella alta between a control cohort and patients with patellar tendinopathy by the sagittal patellar flexion angle (SPFA) measurement. METHODS: Magnetic resonance imaging (MRI) scans of the knee were obtained from a sports imaging facility and screened to select patients with anterior knee pain. This symptomatic group was divided into two patient cohorts: those with and without MRI features of patellar tendinopathy. Lateral knee radiographs were reviewed and SPFA, knee flexion angle and Insall-Salvati ratio (IS) were measured from the radiographs by two independent reviewers. RESULTS: A total of 99 patients consisting of 48 patellar tendinopathy patients and 51 control patients were included. There was a significantly higher mean patellar height (p = 0.002, d = 0.639) and a greater patella alta incidence in the patellar tendinopathy cohort (25.0%) compared to the controls (3.9%) (p = 0.022, d = 0.312). Insall-Salvati ratio measurements showed no difference in patella alta incidence between tendinopathy and control cohorts. There was excellent inter- and intra-observer reliability of SPFA measurements (ICC 0.99). CONCLUSION: This is the first study to demonstrate a greater incidence of patella alta in patellar tendinopathy patients compared to controls. A greater patella alta incidence amongst patellar tendinopathy patients as defined by SPFA was found to be clinically relevant, as it suggests these patients may comprise the recalcitrant patient subgroup who do not improve with current surgical intervention and may therefore benefit from a biomechanical surgical solution. LEVEL OF EVIDENCE: III.
Subject(s)
Patella , Tendinopathy , Humans , Incidence , Patella/diagnostic imaging , Range of Motion, Articular , Reproducibility of Results , Tendinopathy/diagnostic imaging , Tendinopathy/epidemiologyABSTRACT
Advancements in motion sensing technology can potentially allow clinicians to make more accurate range-of-motion (ROM) measurements and informed decisions regarding patient management. The aim of this study was to systematically review and appraise the literature on the reliability of the Kinect, inertial sensors, smartphone applications and digital inclinometers/goniometers to measure shoulder ROM. Eleven databases were screened (MEDLINE, EMBASE, EMCARE, CINAHL, SPORTSDiscus, Compendex, IEEE Xplore, Web of Science, Proquest Science and Technology, Scopus, and PubMed). The methodological quality of the studies was assessed using the consensus-based standards for the selection of health Measurement Instruments (COSMIN) checklist. Reliability assessment used intra-class correlation coefficients (ICCs) and the criteria from Swinkels et al. (2005). Thirty-two studies were included. A total of 24 studies scored "adequate" and 2 scored "very good" for the reliability standards. Only one study scored "very good" and just over half of the studies (18/32) scored "adequate" for the measurement error standards. Good intra-rater reliability (ICC > 0.85) and inter-rater reliability (ICC > 0.80) was demonstrated with the Kinect, smartphone applications and digital inclinometers. Overall, the Kinect and ambulatory sensor-based human motion tracking devices demonstrate moderate-good levels of intra- and inter-rater reliability to measure shoulder ROM. Future reliability studies should focus on improving study design with larger sample sizes and recommended time intervals between repeated measurements.
Subject(s)
Shoulder Joint , Shoulder , Humans , Range of Motion, Articular , Reproducibility of Results , Upper ExtremityABSTRACT
Unfortunately, 3rd author's first name was incorrectly published in the original publication. The complete correct name is given below.
ABSTRACT
PURPOSE: Three-dimensional printing (3DP), or additive manufacturing, is an emergent fabrication technology for surgical devices. As a production method, 3DP enables physical realisation of surgical implants from geometrically complex digital-models in computer-aided design. Spine surgery has been an innovative adopter of 3DP technology for both patient-specific (PS) and market-available 'Off-The-Shelf' (OTS) implants. The present study assessed clinical evidence for efficacy and safety of both PS and OTS 3DP spinal implants through review of the published literature. The aim was to evaluate the clinical utility of 3DP devices for spinal surgery. METHODS: A systematic literature review of peer-reviewed papers featured on online medical databases evidencing the application of 3DP (PS and OTS) surgical spine implants was conducted in accordance with PRISMA guidelines. RESULTS: Twenty-two peer-reviewed articles and one book-chapter were eligible for systematic review. The published literature was limited to case reports and case series, with a predominant focus on PS designs fabricated from titanium alloys for surgical reconstruction in cases where neoplasia, infection, trauma or degenerative processes of the spine have precipitated significant anatomical complexity. CONCLUSION: PS and 3DP OTS surgical implants have demonstrated considerable utility for the surgical management of complex spine pathology. The reviewed literature indicated that 3DP spinal implants have also been used safely, with positive surgeon- and patient-reported outcomes. However, these conclusions are tentative as the follow-up periods are still relatively short and the number of high-powered studies was limited. Single case and small case series reporting would benefit greatly from more standardised reporting of clinical, radiographic and biomechanical outcomes. These slides can be retrieved under Electronic Supplementary Material.
Subject(s)
Plastic Surgery Procedures , Prostheses and Implants , Computer-Aided Design , Humans , Printing, Three-Dimensional , TitaniumABSTRACT
The study aimed to evaluate the comparative osteoconductivity of three commercially available bone void fillers containing gentamicin with respect to new bone, growth, host tissue response and resorption of the implant material. Defects were created in the cancellous bone of the distal femur and proximal tibia of 12-skeletally mature sheep and filled with three commercially available bone void fillers containing gentamicin (Stimulan-G, Cerament-G, Herafill-G). Peripheral blood was taken pre-operatively and at the time of implantation, as well as at intermittent timepoints following surgery to determine systemic gentamicin levels (5-,15- and 30- minutes, 1, 2, 3, 6, 12, 24, 48- and 72-hours, 3-, 6- and 12-weeks). Decalcified, embedded samples were stained with haematoxylin and eosin (H&E) and used to assess the host tissue response and the formation of new bone in the presence of test implant materials. No adverse reactions were noted at harvest at any time points for any cancellous implantation sites with the various implant materials. Comparative microCT analysis of the Stimulan-G, Cerament-G and Herafill-G test materials revealed a similar increase in bone surface area and volume between animals implanted with Stimulan-G or Cerament-G test materials. Animals implanted with Herafill-G test materials demonstrated the lowest increases in bone volume and surface area of the test materials tested, at levels similar to the negative control sites. By 12-weeks, Stimulan-G defects were completely closed with mature bone and bone marrow whilst the Cerament-G material was still present after 12 weeks by histological examination. In conclusion, this study demonstrated differences in the bone regenerative capacity of a range of bone void fillers in an in vivo setting.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bone Regeneration/physiology , Bone Substitutes/chemistry , Bone and Bones/drug effects , Femur/physiology , Tibia/physiology , Animals , Biocompatible Materials , Bone Resorption , Bone and Bones/pathology , Calcium Sulfate/chemistry , Dose-Response Relationship, Drug , Drug Combinations , Durapatite/chemistry , Gentamicins/pharmacology , Materials Testing , Regeneration , Sheep , X-Ray MicrotomographyABSTRACT
PURPOSE: Patellar height measurements on lateral radiographs are dependent on knee flexion which makes standardisation of measurements difficult. This study described a plain radiographic measurement of patellar sagittal height which reflects patellofemoral joint kinematics and can be used at all degrees of flexion. METHODS: The study had two parts. Part one involved 44 normal subjects to define equations for expected patellar position based on the knee flexion angles for three new patellar height measurements. A mixed model regression with random effect for individual was used to define linear and polynomial equations for expected patellar position relating to three novel measurements of patella height: (1) patellar progression angle (trochlea), (2) patellar progression angle (condyle) and (3) sagittal patellar flexion. Part two was retrospective and involved applying these measurements to a surgical cohort to identify differences between expected and measured patellar position pre- and post-operatively. RESULTS: All three measurements provided insight into patellofemoral kinematics. Sagittal patellar flexion was the most useful with the least residual error, was the most reliable, and demonstrated the greatest detection clinically. CONCLUSIONS: Clinically applied radiographic measurements have been described for patellar height which reflect the sagittal motion of the patella and can be used regardless of the degree of flexion in which the radiograph was taken. The expected sagittal patellar flexion linear equation should be used to calculate expected patellar height. LEVEL OF EVIDENCE: IV.
Subject(s)
Patella/anatomy & histology , Patella/physiology , Patellofemoral Joint/anatomy & histology , Patellofemoral Joint/physiology , Adolescent , Adult , Biomechanical Phenomena , Female , Humans , Joint Instability/diagnostic imaging , Joint Instability/pathology , Joint Instability/physiopathology , Joint Instability/surgery , Male , Middle Aged , Movement/physiology , Patella/diagnostic imaging , Patella/surgery , Patellofemoral Joint/diagnostic imaging , Patellofemoral Joint/surgery , Postoperative Period , Prospective Studies , Radiography , Range of Motion, Articular , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Objective assessment of shoulder joint active range of motion (AROM) is critical to monitor patient progress after conservative or surgical intervention. Advancements in miniature devices have led researchers to validate inertial sensors to capture human movement. This study investigated the construct validity as well as intra- and inter-rater reliability of active shoulder mobility measurements using a coupled system of inertial sensors and the Microsoft Kinect (HumanTrak). METHODS: 50 healthy participants with no history of shoulder pathology were tested bilaterally for fixed and free ROM: (1) shoulder flexion, and (2) abduction using HumanTrak and goniometry. The repeat testing of the standardised protocol was completed after seven days by two physiotherapists. RESULTS: All HumanTrak shoulder movements demonstrated adequate reliability (intra-class correlation (ICC) ≥ 0.70). HumanTrak demonstrated higher intra-rater reliability (ICCs: 0.93 and 0.85) than goniometry (ICCs: 0.75 and 0.53) for measuring free shoulder flexion and abduction AROM, respectively. Similarly, HumanTrak demonstrated higher intra-rater reliability (ICCs: 0.81 and 0.94) than goniometry (ICCs: 0.70 and 0.93) for fixed flexion and abduction AROM, respectively. Construct validity between HumanTrak and goniometry was adequate except for free abduction. The differences between raters were predominately acceptable and below ±10°. CONCLUSIONS: These results indicated that the HumanTrak system is an objective, valid and reliable way to assess and track shoulder ROM.
Subject(s)
Range of Motion, Articular , Shoulder , Wearable Electronic Devices , Biomechanical Phenomena , Humans , Reproducibility of ResultsABSTRACT
INTRODUCTION: The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal repair of myelomeningocele (MMC). Neonatal outcome data for 158 of the 183 randomized women were published in The New England Journal of Medicine in 2011. OBJECTIVE: Neonatal outcomes for the complete trial cohort (N = 183) are presented outlining the similarities with the original report and describing the impact of gestational age as a mediator. METHODS: Gestational age, neonatal characteristics at delivery, and outcomes including common complications of prematurity were assessed. RESULTS: Analysis of the complete cohort confirmed the initial findings that prenatal surgery was associated with an increased risk for earlier gestational age at birth. Delivery occurred before 30 weeks of gestation in 11% of neonates that had fetal MMC repair. Adverse pulmonary sequelae were rare in the prenatal surgery group despite an increased rate of oligohydramnios. There was no significant difference in other complications of prematurity including patent ductus arteriosus, sepsis, necrotizing enterocolitis, periventricular leukomalacia, and intraventricular hemorrhage. CONCLUSION: The benefits of prenatal surgery outweigh the complications of prematurity.
Subject(s)
Infant, Newborn, Diseases , Leukomalacia, Periventricular , Meningomyelocele , Female , Gestational Age , Humans , Infant, Low Birth Weight , Infant, Newborn , Meningomyelocele/surgery , PregnancyABSTRACT
Sterile and decellularized allograft tendons are viable biomaterials used in reconstructive surgeries for dense connective tissue injuries. Established allograft processing techniques including gamma irradiation and sodium dodecyl sulfate (SDS) can affect tissue integrity. Supercritical carbon dioxide (SCCO2) represents a novel alternative that has the potential to decellularize and sterilize tendons with minimized exposure to denaturants, shortened treatment time, lack of toxic residues, and superior tissue penetration, and thus efficacy. This study attempted to develop a single-step hybrid decellularization and sterilization protocol for tendons that involved SCCO2 treatment with various chemical additives. The processed tendons were evaluated with mechanical testing, histology, scanning electron microscopy (SEM), and Fourier-transform infrared (FTIR) spectroscopy. Uniaxial mechanical testing showed that tendons treated with SCCO2 and additive NovaKillTM Gen2 and 0.1% SDS had significantly higher (p < 0.05) ultimate tensile stress (UTS) and Young's modulus compared to gamma-irradiated and standard-SDS-treated tendons. This was corroborated by the ultrastructural intactness of SCCO2-treated tendons as examined by SEM and FTIR spectroscopy, which was not preserved in gamma-irradiated and standard SDS-treated tendons. However, complete decellularization was not achieved by the experimented SCCO2-SDS protocols used in this study. The present study therefore serves as a concrete starting point for development of an SCCO2-based combined sterilization and decellularization protocol for allograft tendons, where additive choice is to be optimized.
Subject(s)
Allografts/drug effects , Tendons/drug effects , Tissue Transplantation/methods , Tissue and Organ Harvesting/methods , Allografts/radiation effects , Allografts/transplantation , Animals , Carbon Dioxide/pharmacology , Elastic Modulus , Gamma Rays , Sheep , Sodium Dodecyl Sulfate/pharmacology , Tendons/radiation effects , Tendons/transplantation , Tensile StrengthABSTRACT
Antimicrobial resistance is a multifaceted crisis, imposing a serious threat to global health. The traditional antibiotic pipeline has been exhausted, prompting research into alternate antimicrobial strategies. Inspired by nature, antimicrobial peptides are rapidly gaining attention for their clinical potential as they present distinct advantages over traditional antibiotics. Antimicrobial peptides are found in all forms of life and demonstrate a pivotal role in the innate immune system. Many antimicrobial peptides are evolutionarily conserved, with limited propensity for resistance. Additionally, chemical modifications to the peptide backbone can be used to improve biological activity and stability and reduce toxicity. This review details the therapeutic potential of peptide-based antimicrobials, as well as the challenges needed to overcome in order for clinical translation. We explore the proposed mechanisms of activity, design of synthetic biomimics, and how this novel class of antimicrobial compound may address the need for effective antibiotics. Finally, we discuss commercially available peptide-based antimicrobials and antimicrobial peptides in clinical trials.
Subject(s)
Anti-Bacterial Agents , Bacteria/drug effects , Bacterial Infections/drug therapy , Drug Design , Pore Forming Cytotoxic Proteins , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Humans , Pore Forming Cytotoxic Proteins/pharmacology , Pore Forming Cytotoxic Proteins/therapeutic useABSTRACT
Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineage-committed cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor-AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.
Subject(s)
Azacitidine/pharmacology , Cellular Reprogramming , Induced Pluripotent Stem Cells/metabolism , Mesenchymal Stem Cells/metabolism , Platelet-Derived Growth Factor/pharmacology , Animals , Cells, Cultured , Induced Pluripotent Stem Cells/cytology , Mesenchymal Stem Cells/cytology , Mice , Mice, Transgenic , Organ Specificity/physiologyABSTRACT
BACKGROUND: It is possible that the relative lack of progress in treatment outcomes among adolescent and young adult (AYA) patients with cancer is caused by a difference in disease biology compared with the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive and has a poorer prognosis in AYA patients than in older adult patients. METHODS: To further understand the molecular basis for this difference, whole-exome sequencing was conducted on a cohort of 30 adult, 30 AYA, and 2 pediatric colon cancers. RESULTS: A statistically significant difference in mutational frequency was observed between AYA and adult samples in 43 genes, including ROBO1, MYC binding protein 2 (MYCBP2), breast cancer 2 (early onset) (BRCA2), MAP3K3, MCPH1, RASGRP3, PTCH1, RAD9B, CTNND1, ATM, NF1; KIT, PTEN, and FBXW7. Many of these mutations were nonsynonymous, missense, stop-gain, or frameshift mutations that were damaging. Next, RNA sequencing was performed on a subset of the samples to confirm the mutations identified by exome sequencing. This confirmation study verified the presence of a significantly greater frequency of damaging mutations in AYA compared with adult colon cancers for 5 of the 43 genes (MYCBP2, BRCA2, PHLPP1, TOPORS, and ATR). CONCLUSIONS: The current results provide the rationale for a more comprehensive study with a larger sample set and experimental validation of the functional impact of the identified variants along with their contribution to the biologic and clinical characteristics of AYA colon cancer. Cancer 2018;124:1070-82. © 2017 American Cancer Society.
Subject(s)
Colon/metabolism , Colonic Neoplasms/genetics , Exome Sequencing/methods , Genetic Predisposition to Disease/genetics , Mutation , Adolescent , Adult , Aged , Aged, 80 and over , Colon/pathology , Colonic Neoplasms/pathology , Female , Gene Expression Profiling/methods , Gene Frequency , Humans , Male , Middle Aged , Young AdultABSTRACT
PURPOSE: Antenatally diagnosed ventriculomegaly (VM) requires the balance of risks of neurological injury with premature delivery. The purpose of this study was to evaluate outcomes related to early elective delivery due to fetal VM at our institution. METHODS: We retrospectively assessed 120 babies (2008-2012) with antenatally diagnosed fetal VM. Inclusion criteria for ("early") cohort were (1) elective delivery occurred for expedited neurosurgical intervention between 32 and 36 weeks EGA and (2) fetal VM noted on official antenatal ultrasound. The comparative "near term" cohort differed only in that delivery occurred at 37+ weeks EGA. Statistical significance for comparative analyses set a priori at p < 0.05. RESULTS: Babies electively delivered early had a lower birthweight (p < 0.0001), greater ventricle width (p < 0.0001), and underwent initial CSF diversion sooner (p = 0.014). The early cohort (n = 22), compared to near term (n = 50), had a lower birthweight (p < 0.0001), greater ventricle width (p < 0.0001), and underwent initial CSF diversion sooner (p = 0.014). The early cohort required more repeat procedures: (45 vs. 22% p = 0.021), and VPS removals after VPS infections (41 vs. 12%, p = 0.010). Additionally, newborn respiratory failure (32 vs. 6%, p = 0.037) was more common. Finally, of four babies who died in the early cohort, 2/4 died for prematurity-associated pulmonary hypoplasia. CONCLUSIONS: While early elective delivery for fetal VM expedites intervention for rapidly expanding ventricles, few benefits were identified. Our study concluded those infants that were delivered earlier had increased VPS infections, repeat neurosurgical procedures, and medical co-morbidities. A multi-institutional prospective observational study would be needed in order to confirm the clinical implications of such practice.
Subject(s)
Cesarean Section/methods , Elective Surgical Procedures/methods , Hydrocephalus/surgery , Postoperative Complications/etiology , Postoperative Complications/surgery , Ventriculoperitoneal Shunt/adverse effects , Cohort Studies , Female , Fetus , Gestational Age , Humans , Infant , Infant, Newborn , Intensive Care Units, Neonatal , Male , Prenatal Diagnosis , Statistics, NonparametricABSTRACT
Tendon allografts, when autograft options are limited or when obtaining an autograft is not aligned with the patients' best interest, play an important role in tendon and ligament reconstruction. To minimize the risk of infectious disease transmission tissue banks perform screening tests and the allografts cleaned are sterilized. The current study examines and compares the initial mechanical properties and histological appearance of supercritical CO2 (SCCO2)-treated and gamma-irradiated porcine extensor tendons. Thirty intact porcine forelimb extensor tendons randomized equally into three groups: control group, gamma-irradiation group, and SCCO2-treated group. Once treated, histological assessment and histomorphologic measurements were made on the histological sections obtained from each tendon while stiffness and ultimate failure loads were evaluated from tensile testing. Histological evaluation of gamma-irradiated tendons showed significant disruption to the hierarchical morphology of the fascicle bundles, which was not evident in SCCO2-treated specimens. Histomorphologic measurements showed a significant increase for measured dead space (void) between tendon fibrils of the gamma-irradiated group comparing to both control and SCCO2 treated groups (p < 0.01). There was a significant reduction in the ultimate failure load for tendons treated by gamma-irradiation compared to the control group (p < 0.05). No statistically significant difference was detected between control and SCCO2-treated tendons in the ultimate failure load. Stiffness values were not significantly different between three-study groups. This study suggests that while gamma-irradiation has a deleterious effect on mechanical properties of tendon tissue, SCCO2 does not alter the biomechanical properties and the histological structure of porcine extensor tendons.