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1.
Zoo Biol ; 43(4): 315-324, 2024.
Article in English | MEDLINE | ID: mdl-38685797

ABSTRACT

The white-bellied pangolin Phataginus tricuspis (Rafinesque 1821) is a semiarboreal species occurring in tropical sub-Saharan Africa. It is the world's most trafficked African pangolin species based on volumes recorded in seizures. Reintroduction of confiscated live pangolins and ex-situ rearing are being explored worldwide as a conservation action. However, the husbandry of seized animals is challenging as the diet of the white-bellied pangolin is poorly known and little studied. We analyzed the stomach contents of dead white-bellied pangolins from two forest-savanna protected areas. Stomach content samples from 13 white-bellied pangolin specimens contained ~165,000 Arthropoda, mostly Hymenoptera (60.34%) and Blattodea (39.66%). Overall, we identified 39 termite and 105 ant species consumed as prey by pangolins. Individual pangolins examined had fed on a maximum of 31 ant species and 13 termite species. The termite and ant species richness varied significantly across the pangolins'Ā last consumed meal. We recorded 24 ant genera dominated by Crematogaster (relative importance [RI] = 17.28). Out of 18 termite genera recorded, the genus Pseudacanthotermes (RI = 17.21) was the most important prey. Ten ant species were preferentially eaten by white-bellied pangolin, with Crematogaster acis being the most common prey species. Four species of termite were most frequently eaten with Pseudacanthotermes militaris being the most abundant. The mean abundance of ants and termites varied among pangolin individuals. The season did not influence the mean abundance of termites eaten by pangolin individuals. However, ant abundance in stomach contents was significantly higher in the dry season. An improved understanding of pangolin feeding behavior and prey selection may help inform conservation husbandry efforts. For example, nutritional analysis of the food eaten by wild pangolins can guide the development of nutritional diets for captive pangolins.


Subject(s)
Ants , Diet , Isoptera , Pangolins , Animals , Cameroon , Ants/physiology , Isoptera/physiology , Diet/veterinary , Pangolins/physiology , Ecosystem , Forests , Gastrointestinal Contents , Feeding Behavior/physiology
2.
J Urol ; 207(3): 573-580, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34694140

ABSTRACT

PURPOSE: Multiparametric magnetic resonance imaging (mpMRI) fails to identify some men with significant prostate cancer. Prostate-specific membrane antigen positron emission tomography/computerized tomography (PSMA PET/CT) is recommended for staging of prostate cancer, but its additional benefit above mpMRI alone in local evaluation for prostate cancer is unclear. The study aim was to evaluate the ability of mpMRI and PSMA PET/CT individually and in combination, to predict tumor location and Gleason score ≥3+4 on robot-assisted laparoscopic radical prostatectomy (RALP) histology. MATERIALS AND METHODS: We retrospectively reviewed 1,123 men with a preoperative mpMRI and 68Ga-PSMA PET/CT prior to a RALP. Tumor locations were collected from both imaging modalities and compared to totally embedded prostate histology. Lowest apparent diffusion coefficient value on mpMRI and the highest maximum standardized uptake value (SUVmax) on 68Ga-PSMA PET/CT were collected on the index lesions to perform analysis on detection rates. RESULTS: Median prostate specific antigen was 6. Median Gleason score on biopsy and RALP histology was 4+3. The index lesion and multifocal tumor detection were similar between mpMRI and 68Ga-PSMA PET/CT (p=0.10; p=0.11). When combining mpMRI and 68Ga-PSMA PET/CT, index Gleason score ≥3+4 cancer at RALP was identified in 92%. Only 10% of patients with Gleason score ≤3+4 on biopsy with an SUVmax <5 were upgraded to ≥4+3 on RALP histology, compared to 90% if the SUVmax was >11. CONCLUSIONS: The addition of a diagnostic 68Ga-PSMA PET/CT to mpMRI can improve the detection of significant prostate cancer and improve the ability to identify men suitable for active surveillance.


Subject(s)
Multiparametric Magnetic Resonance Imaging , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Aged , Biomarkers, Tumor/blood , Gallium Isotopes , Gallium Radioisotopes , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prostate-Specific Antigen/blood , Prostatectomy , Prostatic Neoplasms/surgery , Radioisotopes , Retrospective Studies
3.
Proc Natl Acad Sci U S A ; 113(31): E4513-22, 2016 08 02.
Article in English | MEDLINE | ID: mdl-27432980

ABSTRACT

Biological resurfacing of entire articular surfaces represents an important but challenging strategy for treatment of cartilage degeneration that occurs in osteoarthritis. Not only does this approach require anatomically sized and functional engineered cartilage, but the inflammatory environment within an arthritic joint may also inhibit chondrogenesis and induce degradation of native and engineered cartilage. The goal of this study was to use adult stem cells to engineer anatomically shaped, functional cartilage constructs capable of tunable and inducible expression of antiinflammatory molecules, specifically IL-1 receptor antagonist (IL-1Ra). Large (22-mm-diameter) hemispherical scaffolds were fabricated from 3D woven poly(ƎĀµ-caprolactone) (PCL) fibers into two different configurations and seeded with human adipose-derived stem cells (ASCs). Doxycycline (dox)-inducible lentiviral vectors containing eGFP or IL-1Ra transgenes were immobilized to the PCL to transduce ASCs upon seeding, and constructs were cultured in chondrogenic conditions for 28 d. Constructs showed biomimetic cartilage properties and uniform tissue growth while maintaining their anatomic shape throughout culture. IL-1Ra-expressing constructs produced nearly 1 Āµg/mL of IL-1Ra upon controlled induction with dox. Treatment with IL-1 significantly increased matrix metalloprotease activity in the conditioned media of eGFP-expressing constructs but not in IL-1Ra-expressing constructs. Our findings show that advanced textile manufacturing combined with scaffold-mediated gene delivery can be used to tissue engineer large anatomically shaped cartilage constructs that possess controlled delivery of anticytokine therapy. Importantly, these cartilage constructs have the potential to provide mechanical functionality immediately upon implantation, as they will need to replace a majority, if not the entire joint surface to restore function.


Subject(s)
Cartilage, Articular/metabolism , Interleukin 1 Receptor Antagonist Protein/metabolism , Osteoarthritis/metabolism , Tissue Engineering/methods , Adipose Tissue/cytology , Adult , Adult Stem Cells/metabolism , Cartilage, Articular/cytology , Cells, Cultured , Chondrocytes/metabolism , Chondrogenesis , Female , Humans , Interleukin 1 Receptor Antagonist Protein/genetics , Middle Aged , Osteoarthritis/genetics , Osteoarthritis/therapy , Reproducibility of Results , Tissue Scaffolds
4.
Proc Natl Acad Sci U S A ; 111(9): E798-806, 2014 Mar 04.
Article in English | MEDLINE | ID: mdl-24550481

ABSTRACT

The ability to develop tissue constructs with matrix composition and biomechanical properties that promote rapid tissue repair or regeneration remains an enduring challenge in musculoskeletal engineering. Current approaches require extensive cell manipulation ex vivo, using exogenous growth factors to drive tissue-specific differentiation, matrix accumulation, and mechanical properties, thus limiting their potential clinical utility. The ability to induce and maintain differentiation of stem cells in situ could bypass these steps and enhance the success of engineering approaches for tissue regeneration. The goal of this study was to generate a self-contained bioactive scaffold capable of mediating stem cell differentiation and formation of a cartilaginous extracellular matrix (ECM) using a lentivirus-based method. We first showed that poly-L-lysine could immobilize lentivirus to poly(ƎĀµ-caprolactone) films and facilitate human mesenchymal stem cell (hMSC) transduction. We then demonstrated that scaffold-mediated gene delivery of transforming growth factor Ɵ3 (TGF-Ɵ3), using a 3D woven poly(ƎĀµ-caprolactone) scaffold, induced robust cartilaginous ECM formation by hMSCs. Chondrogenesis induced by scaffold-mediated gene delivery was as effective as traditional differentiation protocols involving medium supplementation with TGF-Ɵ3, as assessed by gene expression, biochemical, and biomechanical analyses. Using lentiviral vectors immobilized on a biomechanically functional scaffold, we have developed a system to achieve sustained transgene expression and ECM formation by hMSCs. This method opens new avenues in the development of bioactive implants that circumvent the need for ex vivo tissue generation by enabling the long-term goal of in situ tissue engineering.


Subject(s)
Cell Differentiation/physiology , Chondrogenesis/physiology , Extracellular Matrix/physiology , Tissue Engineering/methods , Tissue Scaffolds/virology , Transduction, Genetic/methods , Analysis of Variance , Biomechanical Phenomena , DNA Primers/genetics , Flow Cytometry , Gene Transfer Techniques , Humans , Immunohistochemistry , Lentivirus , Mesenchymal Stem Cells/metabolism , Microscopy, Electron, Scanning , Microscopy, Fluorescence , Polyesters , Polylysine , Regenerative Medicine/methods , Transforming Growth Factor beta3/genetics
6.
Am J Obstet Gynecol ; 215(5): 596.e1-596.e8, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27177523

ABSTRACT

BACKGROUND: Uterine fibroids are a significant health problem. These common benign tumors occur in 70-80% of women before age 50Ā years and often cause bleeding and pain and can interfere considerably with daily life. Current treatment options are limited. Fibroids contain substantial amounts of altered and disordered collagens, which contribute to their bulk. Targeting these collagens directly presents a novel treatment approach. OBJECTIVES: We sought to test the hypothesis that a highly purified collagenase Clostridium histolyticum will digest interstitial collagen in uterine fibroids and reduce their stiffness and thereby evaluate the feasibility that this collagenase C histolyticum can be developed into an alternative treatment for fibroids. A secondary objective was to describe the collagen content of the fibroid tissue. STUDY DESIGN: Fibroid tissue cubes (1 cm3; nĀ = 154) were cut from 17 uterine fibroids that were obtained from 7 consented subjects undergoing scheduled hysterectomies. Tissue cubes were injected with diluent, placebo, or highly purified collagenase C histolyticum (0.05, 0.1, or 0.2 mg/cube) and incubated at 37Ā°C for 24, 48, 72, or 96 hours. At each time point, 6 noninjected control cubes were also evaluated. Tissue cubes were photographed before and after incubation. Myometrial samples (nĀ = 21) were alsoĀ evaluated. Stiffness was quantified through rheometry by measuring complex shear moduli of the tissues. Percent fibrosis was determined by computerized analysis of Masson-trichrome-stained slides. Digestion of collagen fibrils was confirmed by transmission electron microscopy. RESULTS: Fibrosis in untreated fibroids ranged from 37% to 77%, reflecting the collagen-rich nature of these tumors. After treatment with collagenase for 96 hours, fibrosis ranged from 5.3% to 2.4%. Transmission electron microscopy confirmed complete digestion of collagen fibrils. Tissue stiffness was reduced with all 3 doses of collagenase treatment and at all 4 time points. Longer incubation times with collagenase caused greater reduction in stiffness, and treated cubes lost their cuboidal shape and had gelatinous/liquefied centers. At 96 hours the stiffness in tissues treated with the lowest dose was reduced to 966 Ā± 106 Pascal compared with the diluent-treated control at the same time (5323 Ā± 903 Pascal; P < .0001; by analysis of variance with Tukey-Kramer). CONCLUSION: Uterine fibroids have a high content of collagen that can be effectively digested by highly purified collagenase C histolyticum, resulting in reduced tissue stiffness. Loss of stiffness may decrease bulk symptoms inĀ vivo and possibly lead to shrinkage of fibroids through changed mechanotransduction, leading ultimately to reduced fibroid symptoms of pain and bleeding. Clinical trials are necessary to evaluate the safety and efficacy of collagenase C histolyticum including the rate ofĀ regrowth of fibroids. The data of this study provide a strong rationale forĀ using this purified collagenase in clinical trials as a local treatment for women with fibroids.


Subject(s)
Collagen/drug effects , Leiomyoma/pathology , Microbial Collagenase/pharmacology , Myometrium/drug effects , Uterine Neoplasms/pathology , Collagen/metabolism , Collagen/ultrastructure , Female , Humans , Hysterectomy , In Vitro Techniques , Leiomyoma/metabolism , Leiomyoma/surgery , Mechanotransduction, Cellular/drug effects , Microscopy, Electron, Transmission , Uterine Neoplasms/metabolism , Uterine Neoplasms/surgery
7.
Biotechnol Appl Biochem ; 63(3): 362-70, 2016 May.
Article in English | MEDLINE | ID: mdl-25824972

ABSTRACT

The hepatitis E virus (HEV) capsid antigen expressed in insect cell has been proposed as a candidate subunit vaccine for the prevention of hepatitis E. However, the expression and purification of HEV virus-like particles (VLPs) from insect cells have not been explored. We aimed to optimize the procedure to obtain HEV VLPs. In this study, two conformations of the HEV capsid proteins were expressed in insect cells, VLPs and non-VLPs, and they were purified separately. The physicochemical properties and the humoral immune responses induced by the two forms were analyzed and compared. We found that HEV VLPs were more immunogenic in mice than HEV non-VLPs. Therefore, we optimized the conditions that yielded high VLPs expression in insect cell cultures and developed an efficient purification method. The results suggest that the distinction and isolation of VLPs from non-VLPs are essential to generate a more immunogenic vaccine.


Subject(s)
Hepatitis E virus , Vaccines, Virus-Like Particle/genetics , Animals , Female , Gene Expression , Mice , Sf9 Cells , Spodoptera , Vaccines, Virus-Like Particle/immunology
8.
Immunol Invest ; 44(5): 482-96, 2015.
Article in English | MEDLINE | ID: mdl-26107747

ABSTRACT

Streptococcus pneumoniae is an important pathogen accounting for a large number of deaths worldwide. Due to drawbacks of the current polysaccharide-based vaccine, the most promising way to generate an improved vaccine may be to utilize protection-eliciting pneumococcal proteins. Pneumococcal surface adhesin A (PsaA) and pneumococcal surface protein A (PspA) are two vaccine candidates which have been evaluated against S. pneumoniae infection in animal models or human clinical trials with encouraging results. In this study, the efficacy of the fusion protein PsaA-PspA, which includes PsaA part and PspA part, in inducing immunoprotective effects against fatal pneumococcal challenge was evaluated in an animal model. PspA part of PsaA-PspA fusion protein contains both family1 N-terminal region and family 2 N-terminal clade-defining region of PspA. Immunization with the PsaA-PspA fusion protein induced high levels of antibodies against both PsaA and PspA, which could bind to intact S. pneumoniae strains bearing different PspAs. Ex vivo stimulation of splenocytes from mice immunized with PsaA-PspA induced IL-17A secretion. Mice immunized with PsaA-PspA showed reduced S. pneumoniae levels in the blood and lungs compared with the PBS group after intranasal infection. Finally, mice immunized with PsaA-PspA fusion proteins were protected against fatal challenge with pneumococcal strains expressing different PspAs regardless of the challenge route. These results support the PsaA-PspA fusion protein as a promising vaccine strategy, as demonstrated by its ability to enhance the immune response and stimulate production of high titer antibodies against S. pneumoniae strains bearing heterologous PspAs, as well as confer protection against fatal challenge with PspA family 1 and family 2 strains.


Subject(s)
Adhesins, Bacterial/immunology , Antibodies, Bacterial/biosynthesis , Antigens, Bacterial/immunology , Bacterial Proteins/immunology , Lipoproteins/immunology , Pneumococcal Infections/prevention & control , Pneumococcal Vaccines/immunology , Streptococcus pneumoniae/immunology , Adhesins, Bacterial/genetics , Animals , Antibodies, Bacterial/immunology , Antigens, Bacterial/genetics , Bacterial Proteins/genetics , Drug Evaluation, Preclinical , Female , Interleukin-17/metabolism , Lipoproteins/genetics , Lymphocytes/metabolism , Mice , Mice, Inbred BALB C , Peptide Fragments/genetics , Peptide Fragments/immunology , Rabbits , Recombinant Fusion Proteins/immunology , Spleen/cytology , Streptococcus pneumoniae/genetics , Streptococcus pneumoniae/pathogenicity , Vaccination , Vaccines, Synthetic/immunology , Virulence
9.
Surg Technol Int ; 27: 303-7, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26680414

ABSTRACT

Spinal cord injury (SCI) during revision surgery for persistent multilevel cervical myelopathy (MCM) after an initial anterior procedure is rare. However, the pathophysiology of MCM, even prior to surgery, is a risk-factor for neurological deterioration due to the development of a "sick cord", which reflects pathological changes in the spinal cord that lower the threshold for injury. We report a case of persistent MCM despite a three-level ACDF and corpectomy who developed an incomplete C6 tetraplegia during revision cervical laminectomy and posterior instrumentation. Intraoperative neuromonitoring signal-changes occurred in the absence of mechanical trauma. Postoperative MRI of the cervical spine demonstrated increased T2 hyperintensity and cord expansion at C3 and C4 compared to the pre-laminectomy MRI. The patient has not made improvements in her neurological status at 13 months postoperatively. The pathophysiology of MCM is discussed in addition to perioperative imaging, neuromonitoring, and use of steroids.


Subject(s)
Cervical Vertebrae/surgery , Laminectomy/adverse effects , Quadriplegia/etiology , Spinal Cord Diseases/surgery , Aged , Female , Humans
10.
Adv Funct Mater ; 23(47): 5833-5839, 2013 Dec 17.
Article in English | MEDLINE | ID: mdl-24578679

ABSTRACT

The development of synthetic biomaterials that possess mechanical properties that mimic those of native tissues remains an important challenge to the field of materials. In particular, articular cartilage is a complex nonlinear, viscoelastic, and anisotropic material that exhibits a very low coefficient of friction, allowing it to withstand millions of cycles of joint loading over decades of wear. Here we show that a three-dimensionally woven fiber scaffold that is infiltrated with an interpenetrating network hydrogel can provide a functional biomaterial that provides the load-bearing and tribological properties of native cartilage. An interpenetrating dual-network "tough-gel" consisting of alginate and polyacrylamide was infused into a porous three-dimensionally woven poly(ƎĀµ-caprolactone) fiber scaffold, providing a versatile fiber-reinforced composite structure as a potential acellular or cell-based replacement for cartilage repair.

11.
Ecol Evol ; 13(5)2023 May.
Article in English | MEDLINE | ID: mdl-37181204

ABSTRACT

Pangolin species are notoriously difficult to detect and monitor in the wild and, as a result, commonly used survey techniques fall short in gathering sufficient data to draw confident conclusions on pangolin populations, conservation status, and natural history. The white-bellied pangolin is a semiarboreal species that may be poorly detected in general mammal surveys even with modern techniques such as camera-trapping. As a result, population status information is often derived from hunting, market, and trafficking data. There is therefore a crucial need to improve camera-trap survey methods to reliably detect this species in its natural environment. Here, we test the influence of camera-trap placement strategy on the detectability of the white-bellied pangolin by comparing estimates from targeted ground-viewing camera-trapping and a novel log-viewing placement strategy adapted from local hunters' knowledge. Our results suggest that (1) deploying camera-traps to detect animals walking along logs is an effective strategy for recording several forest species, including the white-bellied pangolin, and (2) that camera-traps targeting logs are more efficient at detecting white-bellied pangolins than camera-traps viewing the ground (>100% increase in detection probability). We also found moderate evidence that there is a relationship between the white-bellied pangolin occurrence at our locality and elevation and weak evidence of an association with distance to the nearest river. Our results suggest an effective new monitoring approach allowing consistent detection of the white-bellied pangolin with moderate survey effort. This highlights the importance of harnessing local knowledge to guide the design of monitoring protocols for cryptic species.

12.
Front Public Health ; 11: 1060479, 2023.
Article in English | MEDLINE | ID: mdl-37181692

ABSTRACT

Background: Despite a scale up of control interventions over the years, malaria remains a major public health and economic concern in Cameroon, contributing considerably to hospitalization and deaths. The effectiveness of control strategies depends on the extent of adherence by the population to national guidelines. This study assessed the influence of human knowledge, attitudes, and practices related to malaria and its control on the prevalence of malaria parasite infection, with implications for the elimination of the disease. Methodology: This is a cross-sectional community and hospital-based study, covering the five ecological and three malaria transmission zones in Cameroon. A pre-tested semi-structured questionnaire was used to document socio-demographic and clinical parameters as well as knowledge, attitudes, and practices toward malaria control and management. Consenting participants were screened for malaria parasite with rapid diagnostic test (mRDT) of the peripheral blood. Association between qualitative variables was determined using the chi-square test and logistic regression analysis. Results: A total of 3,360 participants were enrolled, 45.0% (1,513) of whom were mRDT positive, with 14.0% (451/3,216) and 29.6% (951/3,216) having asymptomatic parasitaemia and malaria, respectively. Although most participants knew the cause, symptoms, and control strategies, with 53.6% (1,000/1,867) expertly knowledgeable about malaria overall, only 0.1% (2/1,763) individuals were fully adherent to malaria control measures. Conclusion: The risk of malaria in Cameroon remains high, with the population considerably knowledgeable about the disease but poorly adherent to national malaria control guidelines. Concerted and more effective strategies aimed at improving knowledge about malaria and adherences to control interventions are necessary to ultimately eliminate the disease.


Subject(s)
Malaria , Plasmodium , Humans , Health Knowledge, Attitudes, Practice , Cameroon/epidemiology , Prevalence , Cross-Sectional Studies , Malaria/epidemiology , Malaria/prevention & control
13.
Science ; 382(6676): 1282-1286, 2023 12 15.
Article in English | MEDLINE | ID: mdl-38096373

ABSTRACT

The white-bellied pangolin (Phataginus tricuspis) is the world's most trafficked mammal and is at risk of extinction. Reducing the illegal wildlife trade requires an understanding of its origins. Using a genomic approach for tracing confiscations and analyzing 111 samples collected from known geographic localities in Africa and 643 seized scales from Asia between 2012 and 2018, we found that poaching pressures shifted over time from West to Central Africa. Recently, Cameroon's southern border has emerged as a site of intense poaching. Using data from seizures representing nearly 1 million African pangolins, we identified Nigeria as one important hub for trafficking, where scales are amassed and transshipped to markets in Asia. This origin-to-destination approach offers new opportunities to disrupt the illegal wildlife trade and to guide anti-trafficking measures.


Subject(s)
Crime , Extinction, Biological , Genomics , Pangolins , Wildlife Trade , Animals , Asia , Genome , Nigeria , Crime/prevention & control , Cameroon
14.
J Environ Manage ; 102: 37-49, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22425877

ABSTRACT

Instream-flow scientists embrace streamflow as the master variable driving aquatic and riparian ecosystems, and that natural flow variability is imperative for river conservation and restoration efforts. Sediment transport, which is critical for maintenance of physical habitats in rivers and floodplains, has received less direct attention from instream-flow practitioners. This article serves to highlight the roles of sediment-transport evaluations in modifying or verifying instream-flow prescriptions based on hydrology alone. Two examples of sediment-transport evaluations are discussed in relation to the Texas Senate Bill 3 Environmental Flows allocation process, a mandate to "develop environmental flow analyses and a recommended flow regime" that "maintain(s) the viability of the state's streams, rivers, and bay and estuary systems" using "reasonably available science". The first example provides an evaluation of effective discharge of suspended-sediment load of the lower Brazos River. The magnitude and frequency of effective discharge occurs between typical high-flow pulses and overbank flows, indicating that hydrologic and physical processes are not optimally coupled in some flow-regime models. The second example utilizes the Hydrology-Based Environmental Flow Regime (HEFR) model to prescribe instream flows for the lower Sabine River, and compares modeled bed-material loads for observed and HEFR-prescribed flow regimes. Results indicate that annual water and sediment yields are greatly reduced for the modeled flow regime. It should be noted, however, that different input variables to the HEFR model would have resulted in different computations of water and sediment yields, reinforcing that instream-flow practitioners should exercise great caution when applying rule-of-thumb procedures to generate flow prescriptions.


Subject(s)
Conservation of Natural Resources , Geologic Sediments , Rivers , Water Movements , Ecosystem , Models, Theoretical , Texas
15.
J Orthop Res ; 40(8): 1721-1734, 2022 08.
Article in English | MEDLINE | ID: mdl-34812518

ABSTRACT

Biological resurfacing of entire articular surfaces represents a challenging strategy for the treatment of cartilage degeneration that occurs in osteoarthritis. Not only does this approach require anatomically sized and functional engineered cartilage, but the inflammatory environment within an arthritic joint may also inhibit chondrogenesis and induce degradation of native and engineered cartilage. Here, we present the culmination of multiple avenues of interdisciplinary research leading to the development and testing of bioartificial cartilage for tissue-engineered resurfacing of the hip joint. The work is based on a novel three-dimensional weaving technology that is infiltrated with specific bioinductive materials and/or genetically-engineered stem cells. A variety of design approaches have been tested in vitro, showing biomimetic cartilage-like properties as well as the capability for long-term tunable and inducible drug delivery. Importantly, these cartilage constructs have the potential to provide mechanical functionality immediately upon implantation, as they will need to replace a majority, if not the entire joint surface to restore function. To date, these approaches have shown excellent preclinical success in a variety of animal studies, including the resurfacing of a large osteochondral defect in the canine hip, and are now well-poised for clinical translation.


Subject(s)
Awards and Prizes , Cartilage Diseases , Cartilage, Articular , Animals , Cartilage, Articular/metabolism , Chondrogenesis , Dogs , Tissue Engineering/methods
16.
Sci Adv ; 7(38): eabi5918, 2021 Sep 17.
Article in English | MEDLINE | ID: mdl-34524840

ABSTRACT

Articular cartilage has unique load-bearing properties but has minimal capacity for intrinsic repair. Here, we used three-dimensional weaving, additive manufacturing, and autologous mesenchymal stem cells to create a tissue-engineered, bicomponent implant to restore hip function in a canine hip osteoarthritis model. This resorbable implant was specifically designed to function mechanically from the time of repair and to biologically integrate with native tissues for long-term restoration. A massive osteochondral lesion was created in the hip of skeletally mature hounds and repaired with the implant or left empty (control). Longitudinal outcome measures over 6 months demonstrated that the implant dogs returned to normal preoperative values of pain and function. Anatomical structure and functional biomechanical properties were also restored in the implanted dogs. Control animals never returned to normal and exhibited structurally deficient repair. This study provides clinically relevant evidence that the bicomponent implant may be a potential therapy for moderate hip osteoarthritis.

17.
Sci Adv ; 7(36): eabj1414, 2021 Sep 03.
Article in English | MEDLINE | ID: mdl-34516920

ABSTRACT

Biologic drug therapies are increasingly used for inflammatory diseases such as rheumatoid arthritis but may cause significant adverse effects when delivered continuously at high doses. We used CRISPR-Cas9 genome editing of iPSCs to create a synthetic gene circuit that senses changing levels of endogenous inflammatory cytokines to trigger a proportional therapeutic response. Cells were engineered into cartilaginous constructs that showed rapid activation and recovery in response to inflammation in vitro or in vivo. In the murine K/BxN model of inflammatory arthritis, bioengineered implants significantly mitigated disease severity as measured by joint pain, structural damage, and systemic and local inflammation. Therapeutic implants completely prevented increased pain sensitivity and bone erosions, a feat not achievable by current clinically available disease-modifying drugs. Combination tissue engineering and synthetic biology promises a range of potential applications for treating chronic diseases via custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals.

18.
Psychol Med ; 40(2): 253-61, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19607749

ABSTRACT

BACKGROUND: Visuospatial working memory (VSWM) deficits have not been investigated specifically in children with dysthymic disorder (DD), although they are associated with impairments in attention that commonly occur in DD. This study investigates VSWM impairment in children with DD. METHOD: A cross-sectional study of VSWM in 6- to 12-year-old children with medication-naive DD (n=26) compared to an age-, gender- and 'performance IQ' (PIQ)-matched healthy control group (n=28) was completed. RESULTS: The DD group demonstrated impairment in VSWM, including impairment in the spatial span and strategy components of VSWM. Furthermore, the VSWM impairment remained after controlling for spatial span. Inattentive symptoms were significantly associated with the VSWM impairment. CONCLUSIONS: This study of children with DD found deficits in performance on VSWM tasks, suggesting that fronto-striatal-parietal neural networks that underlie processes of attention and the executive component of VSWM are dysfunctional in children with DD. These findings further our understanding of DD and suggest more specific interventions that might improve functioning.


Subject(s)
Dysthymic Disorder/psychology , Memory, Short-Term/physiology , Perceptual Disorders/etiology , Space Perception/physiology , Visual Perception/physiology , Attention , Child , Cross-Sectional Studies , Diagnostic and Statistical Manual of Mental Disorders , Dysthymic Disorder/diagnosis , Dysthymic Disorder/epidemiology , Female , Humans , Male , Perceptual Disorders/diagnosis , Perceptual Disorders/epidemiology , Reaction Time
19.
Clin Orthop Relat Res ; 468(9): 2530-40, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20625952

ABSTRACT

BACKGROUND: Cell-based therapies such as tissue engineering provide promising therapeutic possibilities to enhance the repair or regeneration of damaged or diseased tissues but are dependent on the availability and controlled manipulation of appropriate cell sources. QUESTIONS/PURPOSES: The goal of this study was to test the hypothesis that adult subcutaneous fat contains stem cells with multilineage potential and to determine the influence of specific soluble mediators and biomaterial scaffolds on their differentiation into musculoskeletal phenotypes. METHODS: We reviewed recent studies showing the stem-like characteristics and multipotency of adipose-derived stem cells (ASCs), and their potential application in cell-based therapies in orthopaedics. RESULTS: Under controlled conditions, ASCs show phenotypic characteristics of various cell types, including chondrocytes, osteoblasts, adipocytes, neuronal cells, or muscle cells. In particular, the chondrogenic differentiation of ASCs can be induced by low oxygen tension, growth factors such as bone morphogenetic protein-6 (BMP-6), or biomaterial scaffolds consisting of native tissue matrices derived from cartilage. Finally, focus is given to the development of a functional biomaterial scaffold that can provide ASC-based constructs with mechanical properties similar to native cartilage. CONCLUSIONS: Adipose tissue contains an abundant source of multipotent progenitor cells. These cells show cell surface marker profiles and differentiation characteristics that are similar to but distinct from other adult stem cells, such as bone marrow mesenchymal stem cells (MSCs). CLINICAL RELEVANCE: The availability of an easily accessible and reproducible cell source may greatly facilitate the development of new cell-based therapies for regenerative medicine applications in the musculoskeletal system.


Subject(s)
Adult Stem Cells/physiology , Cell Differentiation , Cell Lineage , Multipotent Stem Cells/physiology , Musculoskeletal System/cytology , Subcutaneous Fat/cytology , Tissue Engineering/methods , Adult , Adult Stem Cells/metabolism , Animals , Awards and Prizes , Cartilage, Articular/injuries , Cartilage, Articular/surgery , Cell Culture Techniques , Chondrogenesis , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Multipotent Stem Cells/metabolism , Oxygen/metabolism , Phenotype , Regeneration , Stem Cell Transplantation , Tissue Scaffolds
20.
BMJ Case Rep ; 13(8)2020 Aug 11.
Article in English | MEDLINE | ID: mdl-32784238

ABSTRACT

The COVID-19 pandemic has had a significant impact on the structure and operation of healthcare services worldwide. We highlight a case of a 64-year-old man who presented to the emergency department with acute dyspnoea on a background of a 2-week history of fever, dry cough and shortness of breath. On initial assessment the patient was hypoxic (arterial oxygen saturation (SaO2) of 86% on room air), requiring 10 L/min of oxygen to maintain 98% SaO2 Examination demonstrated left-sided tracheal deviation and absent breath sounds in the right lung field on auscultation. A chest radiograph revealed a large right-sided tension pneumothorax which was treated with needle thoracocentesis and a definitive chest drain. A CT pulmonary angiogram demonstrated segmental left lower lobe acute pulmonary emboli, significant generalised COVID-19 parenchymal features, surgical emphysema and an iatrogenic pneumatocoele. This case emphasises the importance of considering coexisting alternative diagnoses in patients who present with suspected COVID-19.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/complications , Pneumonia, Viral/complications , Pneumothorax/complications , Pulmonary Embolism/complications , Anti-Bacterial Agents/therapeutic use , Anticoagulants/therapeutic use , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Drainage , Humans , Lung/diagnostic imaging , Male , Middle Aged , Oxygen Inhalation Therapy , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/therapy , Pneumothorax/diagnostic imaging , Pneumothorax/therapy , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/drug therapy , Radiography, Thoracic , SARS-CoV-2 , Tinzaparin/therapeutic use , Tomography, X-Ray Computed
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