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INTRODUCTION: Anatomic total shoulder arthroplasty (TSA) is a common surgical intervention for various shoulder pathologies, predominantly glenohumeral osteoarthritis. While generally considered safe and effective, complications remain a challenge. Short stem implants, aim to preserve bone stock and reduce complications. However, concerns about a specific short stem implant (Univers Apex; Arthrex, Naples, FL, USA) have surfaced due to high reported rates relatively early aseptic loosening. METHODS: This retrospective study analyzed 116 consecutive TSA patients with Univers Apex implants from 2004 to 2022. 15 revision cases were assessed for radiographic loosening, and explanted implants were examined for damage using a 0-3 scale. Histopathological analysis evaluated cellular responses to wear debris. RESULTS: Of the patients, 13% (15/116) required revision at 23.2 months on average. A distinct radiographic loosening pattern was identified, with humeral component subsidence and thinning of the proximal humeral cortex. Histopathology revealed a robust inflammatory response to wear debris, with a potential association between macrophage infiltration, hinge damage, and polyethylene wear. CONCLUSION: This study reveals a notable rate of early aseptic humeral loosening with the Univers Apex short stem implant, emphasizing concerns raised in previous reports and providing a potential explanation for the high rate of early failure. Surgeons should exercise caution and closely monitor patients with this implant design.
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PURPOSE: To systematically review the literature to provide an updated evaluation of postoperative clinical outcomes, return to play (RTP), and postoperative complications after primary ulnar collateral ligament reconstruction (UCLR) in throwing and nonthrowing athletes at minimum 2-year follow-up. METHODS: A literature search was performed on November 25, 2023, by querying the Embase, PubMed, and Scopus online databases using the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The inclusion criteria consisted of Level I to IV human clinical studies reporting postoperative outcomes and/or complications after primary UCLR with minimum 2-year follow-up. The exclusion criteria consisted of non-English-language studies; biomechanical, animal, and cadaveric studies; review articles; letters to the editor; and studies not reporting postoperative outcomes or complications. Study quality was evaluated using the Methodological Index for Non-Randomized Studies criteria. The incidence of reported complications among the included studies was extracted. Clinical outcome scores included the Kerlan-Jobe Orthopaedic Clinic Shoulder & Elbow (KJOC) score, Andrews-Timmerman (AT) score, and satisfaction score. RTP data were also extracted. RESULTS: A total of 21 studies published from 2006 to 2023, consisting of 2,452 patients (2,420 male patients) with a mean age of 21.7 years (mean range, 12-65 years) and mean follow-up period of 50.5 months (mean range, 24-151.2 months), were included. The mean Methodological Index for Non-Randomized Studies score was 16 (range, 13-20). A total of 46% of patients (1,138 of 2,452) underwent concomitant ulnar nerve transposition. Palmaris graft was the most frequently used method (66.6%; n = 1,799), followed by hamstring graft (26.0%, n = 703). At the final follow-up, mean postoperative KJOC scores ranged from 72.0 to 88.0; mean AT scores, from 83.6 to 98.3; and mean satisfaction scores, from 86.1 to 98.3. The overall RTP rate ranged from 62.5% to 100% at a mean range of 9.5 to 18.5 months. The total incidence of complications ranged from 0% to 31.8%, with 0% to 7.4% of patients undergoing revision surgery. CONCLUSIONS: UCLR was commonly performed using a palmaris graft, with concomitant ulnar nerve transposition reported in 46% of patients. At a mean follow-up of 50.5 months, mean postoperative KJOC scores ranged from 72 to 98.3, AT scores ranged from 83.6 to 98.3, and satisfaction scores ranged from 86.1 to 98.3, with variable RTP rates. LEVEL OF EVIDENCE: Level IV, systematic review of Level II to IV studies.
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Background: Patients use the Internet to learn information about injuries, yet online content remains largely unstudied. This study analyzed patient questions posed online regarding ulnar collateral ligament (UCL) tears or UCL surgical management. Methods: Three separate search strings about UCL tear and UCL surgery were queried on the Google search engine. The 300 most commonly asked questions were compiled for each topic and associated webpage information was collected from the "People also ask" section. Questions were categorized using the Rothwell classification and webpages by Journal of the American Medical Association (JAMA) benchmark criteria. Results: The most frequent UCL tear questions were "how long does it take to heal a torn UCL?" and "what is nonsurgical treatment for the UCL?" The most frequent UCL surgery question was "can you retear your UCL after surgery?" The Rothwell classification of questions for UCL tear/UCL surgery was 55%/32% policy, 38%/57% fact, and 7%/11% value with highest subcategories being indications/management (46%/25%) and technical details (24%/25%). The most common webpages were academic (39%/29%) and medical practice (24%/26%). Mean JAMA score for all 600 webpages was low (1.2), with journals (mean = 3.4) having the highest score. Medical practice (mean = 0.5) and legal websites (mean = 0.0) had the lowest JAMA scores. Only 30% of webpages provided UCL-specific information. Conclusion: Online UCL patient questions commonly pertain to technical details and injury management. Webpages suggested by search engines contain information specific to UCL tears and surgery only one-third of the time. The quality of most webpages provided to patients is poor, with minimal source transparency.
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PURPOSE: To compare patient-reported outcomes, failure rates, risk factors for failure, and complications in patients with bucket-handle meniscus tears (BHMTs) undergoing repair with inside-out (IO) versus all-inside (AI) techniques. METHODS: A literature search was performed using the PubMed, Embase, and Scopus databases from database inception to August 2023 according to the 2020 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. The inclusion criteria consisted of Level I to IV clinical studies published in the past 10 years with greater than 2 years of follow-up that evaluated patient-reported outcome scores and/or the incidence of failure after IO or AI repairs for BHMTs. Clinical studies not reporting outcomes or failure rates, older studies using outdated implants, animal studies, reviews, letters to the editor, case reports, cadaveric studies, and articles not written in the English language or with English-language translation were excluded. Study quality was assessed using the Methodological Index for Non-randomized Studies (MINORS) criteria. Outcomes were reported as ranges and qualitatively compared. RESULTS: A total of 16 studies published from 2013 to 2023, consisting of 1,062 patients with BHMTs, were identified. Thirteen studies (14 cohorts, 649 patients) reported on AI repair (mean age range, 23.7-32 years) and 7 studies (7 cohorts, 413 patients) reported on IO repair (mean age range, 16.7-34.6 years). Both groups had improved postoperative Lysholm and Tegner scores. Decreased range of motion was the most commonly reported complication in the AI group (range, 2.6%-4%), whereas adhesions for arthrofibrosis were the most commonly reported complication in the IO group (n = 12; range, 6%-7.9%). The overall reported failure rate ranged from 6.9% to 20.5% within the AI group and from 0% to 20% within the IO group. CONCLUSIONS: AI and IO repair techniques for BHMTs both result in improved Lysholm and Tegner scores. However, broad ranges of failure are reported in the literature, with overall failure rates ranging from 6.9% to 20.5% after AI repair and from 0% to 20% after IO repair. Younger age and isolated medial BHMT repair are the most frequently reported risk factors for the AI technique, whereas postoperative stiffness is the most frequently reported complication after both repair techniques. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies.
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BACKGROUND: While increased posterior tibial slope (PTS) is an established risk factor for anterior cruciate ligament tears, the association between tibial slope and meniscal posterior root tears is not well-defined. PURPOSE: To summarize the available literature evaluating the association between PTS and meniscus root injuries compared with patients without root tears. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A literature search was performed using the Scopus, PubMed, and Embase databases. Human clinical studies evaluating the associations between the medial tibial slope (MTS), lateral tibial slope (LTS), lateral-to-medial (L-to-M) slope asymmetry, and the risk of meniscus root tears were included. Patients with medial meniscus posterior root tears (MMPRTs) and lateral meniscus posterior root tears (LMPRTs) were compared with a control group without root injury. Study quality was assessed using the methodological index for non-randomized studies criteria. RESULTS: Ten studies with 1313 patients were included (884 patients with root tears; 429 controls). The LMPRT subgroup (n = 284) had a significantly greater LTS (mean ± SD, 7.3°± 1.5° vs 5.7°± 3.91°; P < .001), MTS (5.26°± 1.2° vs 4.8°± 1.25°; P < .001), and increased L-to-M asymmetry (2.3°± 1.3° vs 0.65°± 0.5°; P < .001) compared with controls. The MMPRT group (n = 600) had significantly increased MTS relative to controls (8.1°± 2.5° vs 4.3°± 0.7°; P < .001). Furthermore, there was a higher incidence of noncontact injuries (79.3%) and concomitant ramp lesions (56%) reported in patients with LMPRT. CONCLUSION: Increased MTS, LTS, and L-to-M slope asymmetry are associated with an increased risk of LMPRTs, while increased MTS is associated with MMPRTs. Surgeons should consider how proximal tibial anatomy increases the risk of meniscus root injury.
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PURPOSE: To identify the preoperative risk factors associated with contralateral symptom development and surgical intervention for patients presenting with unilateral femoral acetabular impingement (FAI) syndrome. METHODS: A literature search was performed using PubMed and Scopus computerized databases according to the 2020 Preferred Reporting Items for Systematic Meta-Analyses guidelines. Studies evaluating preoperative risk factors associated with the contralateral progression of FAI were included. Quality assessment was completed using the Methodological Index for Non-Randomized Studies criteria. RESULTS: A total of 5 studies (n = 1,011 patients; mean age, 29.9 years) published from 2013 to 2022 met the inclusion/exclusion criteria. Mean follow-up ranged from 12 to 132 months. The overall rate of contralateral progression of symptomatic FAI ranged from 32.4% to 81%. Increased alpha angle was frequently reported factor associated with contralateral symptom progression, followed by decreased total arc of rotation, decreased internal rotation, reduced neck-shaft angle, and head-neck offset. The incidence rate of progression to contralateral surgery ranged from 15.7% to 24% of patients. Younger age was frequently reported factor associated with contralateral surgical intervention, followed by male sex, increased level of activity, and increased alpha angle. CONCLUSIONS: Increased alpha angle and younger age were commonly reported risk factors associated with an increased risk of symptom development and surgical progression of contralateral FAI, respectively. The overall rate of contralateral progression of symptomatic FAI and the rate of progression to surgical intervention ranged up to 81% and 24%, respectively. This information may help both patients and surgeons to establish expectations regarding development of contralateral hip symptoms and possible need for surgery. LEVEL OF EVIDENCE: Level III; systematic review of Level II-III studies.
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Pinzamiento Femoroacetabular , Articulación de la Cadera , Humanos , Bases de Datos Factuales , Pinzamiento Femoroacetabular/complicaciones , Articulación de la Cadera/cirugía , Factores de RiesgoRESUMEN
Purpose: To compare revision rates and residual postoperative instability after anterior cruciate ligament (ACL) reconstruction based on biological sex. Methods: A systematic review was conducted according to the 2020 PRISMA guidelines. PubMed, Embase, MEDLINE, and Cochrane library databases were queried from database inception through October 2022. Level I and II prospectively-enrolling human clinical studies that compared revision rates and physical examination of postoperative stability after ACL reconstruction between male and female patients were included. Outcomes were stratified by patient sex and quantitatively compared using a χ2 test. Study quality was assessed using the MINORS criteria. Results: Four studies consisting of 406 patients (50% males) with a mean age of 25 years (range, 13.9-62 years) were identified. Mean follow-up time was 34.4 months (range, 22-60 months). Hamstring tendon autografts were used in 62% of ACL reconstructions in males and in 65% of ACL reconstructions in females, whereas bone-patellar tendon-bone autografts were used in 38% and 35% of procedures in males and females, respectively. A residual positive Lachman test result was more frequently reported among females compared to males (5.8% vs 0.6%; P = 0.03). No significant difference in revision rates or residual pivot-shift on examination was observed between males and females (P = 0.38 and P = 0.08, respectively). Conclusion: Female patients undergoing ACL reconstruction have higher reported rates of residual anterior instability with Lachman than male patients. However, no sex-based differences were identified with residual pivot-shift on examination or rate of revision ACL surgery. Level of Evidence: II; Systematic Review of level II studies.
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Purpose: To systematically examine the effects of radiofrequency (RF) ablation or coblation (controlled ablation) on chondrocyte viability following knee chondroplasty in preclinical literature to determine the effectiveness and safety of RF-based techniques. Methods: A literature search was performed in September 2022 using PubMed and Scopus using the following search terms combined with Boolean operators: "chondroplasty," "radiofrequency," "thermal," "knee," "chondral defect," "articular cartilage," and "cartilage." The inclusion criteria consisted of preclinical studies examining the effect of RF ablation or coblation on chondrocytes during knee chondroplasty. Exclusion criteria consisted of studies reporting chondroplasty in joints other than the knee, clinical studies, in vitro studies using animal models, case reports, non-full-text articles, letters to editors, surveys, review articles, and abstracts. The following data were extracted from the included articles: author, year of publication, chondral defect location within the knee and chondral characteristics, RF probe characteristics, cartilage macroscopic description, microscopic chondrocyte description, and extracellular matrix characteristics. Results: A total of 17 articles, consisting of 811 cartilage specimens, were identified. The mean specimen age was 63.4 ± 6.0 (range, 37-89) years. Five studies used monopolar RF devices, 7 studies used bipolar RF devices, whereas 4 studies used both monopolar and bipolar RF devices. Time until cell death during ablation at any power was reported in 5 studies (n = 351 specimens), with a mean time to cell death of 54.4 seconds (mean range, 23.1-64) for bipolar RF and 56.3 seconds (mean range, 12.5-64) for monopolar RF devices. Chondrocyte cell death increased with increased wattage, while treatment time was positively correlated with deeper cell death. Conclusions: In this systematic review, histologic analysis demonstrated that RF-based chondroplasty creates a precise area of targeted chondrocyte death, with minimal evidence of necrosis outside the target zone. Caution must be exercised when performing RF-based chondroplasty due to the risk of cell death with increased application time and wattage. Clinical Relevance: Although RF ablation has demonstrated favorable results in preliminary trials, including smoother cartilage and less damage to the surrounding healthy tissue, the risks versus benefits of the procedure are largely unknown. Caution must be exercised when performing RF-based chondroplasty in the clinical setting due to the risk of cell death with increased application time and wattage.
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Successful anterior cruciate ligament reconstruction depends heavily on accurate placement of the graft within the anatomical insertion of the native anterior cruciate ligament. Inaccurate placement can lead to graft failure and recurrent instability. Flexible guide pins and reamers have been developed to overcome some of the limitations of using transtibial and anteromedial portals to drill femoral tunnels. Early in our experience with flexible instruments, reamer breakage caused complications. We therefore developed a technique that uses a flexible guide pin with a rigid reamer to place the femoral tunnel in an anatomical position. This technique allows placement of longer anatomical tunnels through an anteromedial portal, reduces time spent with the knee in hyperflexion, provides better viewing, poses less risk of damage to the articular cartilage and neurovascular structures, and at a lower cost with less risk of reamer breakage.
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Reconstrucción del Ligamento Cruzado Anterior/instrumentación , Ligamento Cruzado Anterior/cirugía , Articulación de la Rodilla/cirugía , Lesiones del Ligamento Cruzado Anterior , Artroscopía , Clavos Ortopédicos , Fémur/cirugía , HumanosRESUMEN
Transplantation of islet cells is an effective treatment for type 1 diabetes with critically labile metabolic control. However, during islet isolation, blood supply is disrupted, and the transport of nutrients/metabolites to and from the islet cells occurs entirely by diffusion. Adequate oxygen supply is essential for function/survival of islet cells and is the limiting factor for graft integrity. Recently, we developed an immunoisolated chamber system for transplantation of human islets without immunosuppression. This system depended on daily oxygen supply. To provide independence from this external source, we incorporated a novel approach based on photosynthetically-generated oxygen. The chamber system was packed sandwich-like with a slab of immobilized photosynthetically active microorganisms (Synechococcus lividus) on top of a flat light source (LEDs, red light at 660 nm, intensity of 8 µE/m(2)/s). Islet cells immobilized in an alginate slab (500-1,000 islet equivalents/cm(2)) were mounted on the photosynthetic slab separated by a gas permeable silicone rubber-Teflon membrane, and the complete module was sealed with a microporous polytetrafluorethylene (Teflon) membrane (pore size: 0.4 µm) to protect the contents from the host immune cells. Upon illumination, oxygen produced by photosynthesis diffused via the silicone Teflon membrane into the islet compartment. Oxygen production from implanted encapsulated microorganisms was stable for 1 month. After implantation of the device into diabetic rats, normoglycemia was achieved for 1 week. Upon retrieval of the device, blood glucose levels returned to the diabetic state. Our results demonstrate that an implanted photosynthetic bioreactor can supply oxygen to transplanted islets and thus maintain islet viability/functionality.
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Trasplante de Islotes Pancreáticos/instrumentación , Islotes Pancreáticos/metabolismo , Oxígeno/metabolismo , Fotosíntesis , Animales , Diabetes Mellitus Experimental/metabolismo , Humanos , Masculino , Consumo de Oxígeno , Ratas Endogámicas Lew , Reproducibilidad de los Resultados , Synechococcus/metabolismoRESUMEN
We report our staged multimodal treatment of a female infant with a very large complex venolymphatic malformation of the axilla and chest wall. We successfully managed the patient's severely restricted arm mobility and consumptive coagulopathy with surgical debulking followed by medical therapy with the mammalian target of rapamycin inhibitor sirolimus. The diseased burden reduced in size throughout therapy, and hematologic parameters reached and maintained normal levels. Normal health and limb functionality were restored with no observed adverse side effects of medical therapy. This case presents a previously unreported and potentially promising method to treat severe vascular malformations.
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Gd(III) associated with carbon nanomaterials relaxes water proton spins at an effectiveness that approaches or exceeds the theoretical limit for a single bound water molecule. These Gd(III)-labeled materials represent a potential breakthrough in sensitivity for Gd(III)-based contrast agents used for magnetic resonance imaging (MRI). However, their mechanism of action remains unclear. A gadographene library encompassing GdCl3, two different Gd(III)-complexes, graphene oxide (GO), and graphene suspended by two different surfactants and subjected to varying degrees of sonication was prepared and characterized for their relaxometric properties. Gadographene was found to perform comparably to other Gd(III)-carbon nanomaterials; its longitudinal (r1) and transverse (r2) relaxivity is modulated between 12-85 mM-1s-1 and 24-115 mM-1s-1, respectively, depending on the Gd(III)-carbon backbone combination. The unusually large relaxivity and its variance can be understood under the modified Florence model incorporating the Lipari-Szabo approach. Changes in hydration number (q), water residence time (τM), molecular tumbling rate (τR), and local motion (τfast) sufficiently explain most of the measured relaxivities. Furthermore, results implicated the coupling between graphene and Gd(III) as a minor contributor to proton spin relaxation.
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PURPOSE: Monitoring of fibrinogen level is used to predict bleeding during lower extremity tissue plasminogen activator (tPA) infusions for peripheral arterial or venous thrombolysis. This practice is not fully addressed in the literature. MATERIALS AND METHODS: We retrospectively reviewed fibrinogen levels and studied bleeding rate from charts of patients who underwent lower extremity tPA infusions at a single hospital from January 2010 to May 2012. RESULTS: The rate of thrombolytic success did not correlate with fibrinogen level (P = .53). The rate of major bleeding was significantly higher for patients with a fibrinogen level at or below 150 mg/dL (P = .01). Patients whose tPA infusion was terminated within 46 hours had significantly lower rates of major bleeding (P = .01) and thrombolytic failure (P < .01). Periprocedural systolic blood pressure above 160 mm Hg was a risk factor for major bleeding (P = .02). There was no association between concomitant aspirin use (P = .90, .51) or hourly tPA dose (P = .71, .62) and thrombolytic success or major bleeding, respectively. CONCLUSION: Fibrinogen level ≤ 150 mg/dL is associated with increased risk of major bleeding during tPA infusions. We suggest serial fibrinogen measurement as a viable method to monitor bleeding risk during lower extremity tPA infusions.
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Arteriopatías Oclusivas/tratamiento farmacológico , Monitoreo de Drogas/métodos , Fibrinógeno/metabolismo , Fibrinolíticos/administración & dosificación , Extremidad Inferior/irrigación sanguínea , Terapia Trombolítica , Trombosis/tratamiento farmacológico , Activador de Tejido Plasminógeno/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Arteriopatías Oclusivas/sangre , Arteriopatías Oclusivas/diagnóstico , Biomarcadores/sangre , Femenino , Fibrinolíticos/efectos adversos , Hemorragia/sangre , Hemorragia/inducido químicamente , Humanos , Infusiones Intraarteriales , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Minnesota , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Terapia Trombolítica/efectos adversos , Trombosis/sangre , Trombosis/diagnóstico , Factores de Tiempo , Activador de Tejido Plasminógeno/efectos adversos , Resultado del Tratamiento , Trombosis de la Vena/sangre , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/tratamiento farmacológico , Adulto JovenRESUMEN
In this study, a systematic approach has been followed to investigate the fate and transport of single walled carbon nanotubes (SWCNTs) from synthesis to environmentally relevant conditions. Three widely used SWCNT synthesis methods have been investigated in this study including high pressure carbon monoxide (HiPco), SWeNT CoMoCat, and electric arc discharge technique (EA). This study relates the transport of three SWCNTs (HiPco-D, SG65-D, and P2-D) with different synthesis methods and residual catalyst content revealing their influence on the subsequent fate of the nanotubes. To minimize nanotube bundling and aggregation, the SWCNTs were dispersed using the biocompatible triblock copolymer Pluronic, which allowed the comparison in the transport trends among these SWCNTs. After purification, the residual metal catalyst between the SWCNTs follows the trend: HiPco-D > SG65-D > P2-D. The electrophoretic mobility (EPM) and hydrodynamic diameter of SWCNTs remained insensitive to SWCNT type, pH, and presence of natural organic matter (NOM); but were affected by ionic strength (IS) and ion valence (K(+), Ca(2+)). In monovalent ions, the hydrodynamic diameter of SWCNTs was not influenced by IS, whereas larger aggregation was observed for HiPco-D with IS than P2-D and SG65-D in the presence of Ca(2+). Transport of HiPco-D in the porous media was significantly higher than SG65-D followed by P2-D. Release of HiPco-D from porous media was higher than SG65-D followed by P2-D, though negligible amount of all types of SWCNTs (<5%) was released. Both transport and release patterns follow a similar trend to what was observed for residual metal catalysts in SWCNTs. Addition of NOM increased the transport of all SWCNTs primarily due to electrosteric repulsion. HiPco-D was notably more acidic than SG65-D followed by P2-D, which is similar to the transport trend. Overall, it was observed that the synthesis methods resulted in distinctive breakthrough trends, which were correlated to metal content. These findings will facilitate the safe design of environmental friendly SWCNTs by minimizing mobility in aquatic environments.
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Metales/química , Nanotubos de Carbono/química , Contaminantes Químicos del Agua/química , Catálisis , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Luminiscencia , Nanotubos de Carbono/toxicidad , Porosidad , Movimientos del Agua , Contaminantes Químicos del Agua/toxicidadRESUMEN
BACKGROUND: After age, the second largest risk factor for Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype, where APOE4 is associated with lower apoE protein levels, more severer brain pathology, enhanced inflammation and disease. Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE holoprotein. These apoE mimetics greatly improve behavioral outcomes and neuronal survival in head trauma models that display AD pathology and neuronal loss. OBJECTIVE: To determine whether apoE mimetics change behavior, inflammation and pathology in CVND-AD (SwDI-APP/NOS2(-/-)) transgenic mice. METHODS: Starting at 9 months, apoE peptides were subcutaneously administered 3 times per week for 3 months followed by behavioral, histochemical and biochemical testing. RESULTS: Treatment with apoE mimetics significantly improved behavior while decreasing the inflammatory cytokine IL-6, neurofibrillary tangle-like and amyloid plaque-like structures. Biochemical measures matched the visible pathological results. CONCLUSIONS: Treatment with apoE mimetics significantly improved behavior, reduced inflammation and reduced pathology in CVND-AD mice. These improvements are associated with apoE-mimetic-mediated increases in protein phosphatase 2A activity. Testing in additional AD models showed similar benefits, reinforcing this novel mechanism of action of apoE mimetics. These data suggest that the combination of anti-inflammatory and neuroprotective activities of apoE mimetics represents a new generation of potential therapeutics for AD.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Apolipoproteínas E/uso terapéutico , Síntomas Conductuales/tratamiento farmacológico , Encéfalo/metabolismo , Ovillos Neurofibrilares/efectos de los fármacos , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Síntomas Conductuales/etiología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Mutación/genética , Óxido Nítrico Sintasa de Tipo II/deficiencia , Fosfopiruvato Hidratasa/metabolismo , ARN Mensajero/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
AIMS/HYPOTHESIS: Islet transplantation is a promising treatment for type 1 diabetes but is hampered by a shortage of donor human tissue and early failure. Research on islet cell transplantation includes finding new sources of cells and immunoisolation to protect from immune assault and tumourigenic potential. Small islet cell aggregates were studied to determine if their survival and function were superior to intact islets within microcapsules because of reduced oxygen transport limitation and inflammatory mediators. METHODS: Islet cell aggregates were generated by dispersing rat islets into single cells and allowing them to re-aggregate in culture. Rat islets and islet cell aggregates were encapsulated in barium alginate capsules and studied when cultured in low (0.5% or 2%) or normal (20%) oxygen, or transplanted into mice. RESULTS: Encapsulated islet cell aggregates were able to survive and function better than intact islets in terms of oxygen-consumption rate, nuclei counts, insulin-to-DNA ratio and glucose-stimulated insulin secretion. They also had reduced expression of pro-inflammatory genes. Islet cell aggregates showed reduced tissue necrosis in an immunodeficient transplant model and a much greater proportion of diabetic xenogeneic transplant recipients receiving islet cell aggregates (tissue volume of only 85 islet equivalents) had reversal of hyperglycaemia than recipients receiving intact islets. CONCLUSIONS/INTERPRETATION: These aggregates were superior to intact islets in terms of survival and function in low-oxygen culture and during transplantation and are likely to provide more efficient utilisation of islet tissue, a finding of importance for the future of cell therapy for diabetes.
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Agregación Celular , Diabetes Mellitus Experimental/cirugía , Trasplante de Islotes Pancreáticos/métodos , Islotes Pancreáticos/citología , Análisis de Varianza , Animales , Cápsulas/metabolismo , Recuento de Células , Técnicas de Cultivo de Célula , Células Cultivadas , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Necrosis/metabolismo , Ratas , Ratas Sprague-Dawley , Trasplante HeterólogoRESUMEN
The neurovascular unit (NVU) comprises cerebral blood vessels and surrounding astrocytes, neurons, perivascular microglia and pericytes. Astrocytes associated with the NVU are responsible for maintaining cerebral blood flow and ionic and osmotic balances in the brain. A significant proportion of individuals with Alzheimer's disease (AD) have vascular amyloid deposits (cerebral amyloid angiopathy, CAA) that contribute to the heterogeneous nature of the disease. To determine whether NVU astrocytes are affected by the accumulation of amyloid at cerebral blood vessels we examined astrocytic markers in four transgenic mouse models of amyloid deposition. These mouse models represent mild CAA, moderate CAA with disease progression to tau pathology and neuron loss, severe CAA and severe CAA with disease progression to tau pathology and neuron loss. We found that CAA and disease progression both resulted in distinct NVU astrocytic changes. CAA causes a loss of apparent glial fibrillary acidic protein (GFAP)-positive astrocytic end-feet and loss of water channels (aquaporin 4) localized to astrocytic end feet. The potassium channels Kir4.1, an inward rectifying potassium channel, and BK, a calcium-sensitive large-conductance potassium channel, were also lost. The anchoring protein, dystrophin 1, is common to these channels and was reduced in association with CAA. Disease progression was associated with a phenotypic switch in astrocytes indicated by a loss of GFAP-positive cells and a gain of S100 beta-positive cells. Aquaporin 4, Kir4.1 and dystrophin 1 were also reduced in autopsied brain tissue from individuals with AD that also display moderate and severe CAA. Together, these data suggest that damage to the neurovascular unit may be a factor in the pathogenesis of Alzheimer's disease.
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Enfermedad de Alzheimer/fisiopatología , Acuaporina 4/metabolismo , Astrocitos/fisiología , Angiopatía Amiloide Cerebral/fisiopatología , Canales de Potasio/metabolismo , Anciano de 80 o más Años , Precursor de Proteína beta-Amiloide/genética , Animales , Astrocitos/patología , Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Distrofina/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Canal de Potasio Kv1.6 , Masculino , Ratones , Ratones Transgénicos , Óxido Nítrico Sintasa de Tipo II/genética , Canales de Potasio de Rectificación Interna/metabolismo , Nexinas de Proteasas , ARN Mensajero , Receptores de Superficie Celular/genética , Canales de Potasio de la Superfamilia Shaker/metabolismoRESUMEN
Detection of motor dysfunction in genetic mouse models of neurodegenerative disease requires reproducible, standardized and sensitive behavioral assays. We have utilized a center of pressure (CoP) assay in mice to quantify postural sway produced by genetic mutations that affect motor control centers of the brain. As a positive control for postural instability, wild type mice were injected with harmaline, a tremorigenic agent, and the average areas of the 95% confidence ellipse, which measures 95% of the CoP trajectory values recorded in a single trial, were measured. Ellipse area significantly increased in mice treated with increasing doses of harmaline and returned to control values after recovery. We also examined postural sway in mice expressing mutations that mimic frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) (T-279, P301L or P301L-nitric oxide synthase 2 (NOS2)(-/-) mice) and that demonstrate motor symptoms. These mice were then compared with a mouse model of Alzheimer's disease (APPSwDI mice) that demonstrates cognitive, but not motor deficits. T-279 and P301L-NOS2(-/-) mice demonstrated a significant increase in CoP ellipse area compared with appropriate wild type control mice or to mice expressing the P301L mutation alone. In contrast, postural instability was significantly reduced in APPSwDI mice that have cognitive deficits but do not have associated motor deficits. The CoP assay provides a simple, sensitive and quantitative tool to detect motor deficits resulting from postural abnormalities in mice and may be useful in understanding the underlying mechanisms of disease.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedades Neurodegenerativas/fisiopatología , Equilibrio Postural/fisiología , Postura/fisiología , Factores de Edad , Precursor de Proteína beta-Amiloide/genética , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Fenómenos Biomecánicos/métodos , Femenino , Harmalina/efectos adversos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de la Monoaminooxidasa/efectos adversos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Mutación/genética , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/genética , Óxido Nítrico Sintasa de Tipo II/genética , Temblor/inducido químicamente , Temblor/fisiopatologíaRESUMEN
There is a need for simple, quantitative and prospective assays for islet quality assessment that are predictive of islet transplantation outcome. The current state-of-the-art athymic nude mouse bioassay is costly, technically challenging and retrospective. In this study, we report on the ability of 2 parameters characterizing human islet quality: (1) oxygen consumption rate (OCR), a measure of viable volume; and (2) OCR/DNA, a measure of fractional viability, to predict diabetes reversal in nude mice. Results demonstrate that the probability for diabetes reversal increases as the graft's OCR/DNA and total OCR increase. For a given transplanted OCR dose, diabetes reversal is strongly dependent on OCR/DNA. The OCR and OCR/DNA (the 'OCR test') data exhibit 89% sensitivity and 77% specificity in predicting diabetes reversal in nude mice (n = 86). We conclude that the prospective OCR test can effectively replace the retrospective athymic nude mouse bioassay in assessing human islet quality prior to islet transplantation.