RESUMO
The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major challenge for clinical translation of Rett syndrome gene therapy vectors to date. Our team designed a new truncated methyl-CpG-binding protein 2 (MECP2) promoter allowing widespread expression of MECP2 in mice and non-human primates after a single injection into the cerebrospinal fluid without causing overexpression symptoms up to 18 months after injection. Additionally, this new vector is highly efficacious at lower doses compared with previous constructs as demonstrated in extensive efficacy studies performed by two independent laboratories in two different Rett syndrome mouse models carrying either a knockout or one of the most frequent human mutations of Mecp2. Overall, data from this multicenter study highlight the efficacy and safety of this gene therapy construct, making it a promising candidate for first-in-human studies to treat Rett syndrome.
Assuntos
Síndrome de Rett , Humanos , Camundongos , Animais , Síndrome de Rett/genética , Síndrome de Rett/terapia , Síndrome de Rett/metabolismo , Primatas/genética , Terapia Genética , MutaçãoRESUMO
Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.
Assuntos
Produtos Biológicos/efeitos adversos , Terapia Genética/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Atrofias Musculares Espinais da Infância/terapia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Autopsia , Produtos Biológicos/administração & dosagem , DNA/genética , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Vetores Genéticos/genética , Humanos , Lactente , Recém-Nascido , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , RNA Mensageiro/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/mortalidade , Atrofias Musculares Espinais da Infância/patologia , Distribuição Tecidual/efeitos dos fármacosRESUMO
STUDY DESIGN: Controlled laboratory study. OBJECTIVES: To measure the architectural properties of rat supraspinatus muscle after a complete detachment of its distal tendon. METHODS: Supraspinatus muscles were released from the left humerus of 29 Sprague-Dawley rats (mass, 400-450 g), and the animals were returned to cage activity for 2 weeks (n=12), 4 weeks (n=9), or 9 weeks (n=8), before euthanasia. Measurements of muscle mass, pennation angle, fiber bundle length (sarcomere number), and sarcomere length permitted calculation of normalized fiber length, serial sarcomere number, and physiological cross-sectional area. RESULTS: Coronal oblique sections of the supraspinatus confirmed surgical transection of the supraspinatus muscle at 2 weeks, with reattachment by 4 weeks. Muscle mass and length were significantly lower in released muscles at 2 weeks, 4 weeks, and 9 weeks. Sarcomere lengths in released muscles were significantly shorter at 2 weeks but not different by 4 weeks. Sarcomere number was significantly reduced at 2 and 4 weeks, but returned to control values by 9 weeks. The opposing effects of smaller mass and shorter fibers produced significantly smaller physiological cross-sectional area at 2 weeks, but physiological cross-sectional area returned to control levels by 4 weeks. CONCLUSIONS: Release of the supraspinatus muscle produced early radial and longitudinal atrophy of the muscle. The functional implications of these adaptations would be most profound at early time points (particularly relevant for rehabilitation), when the muscle remains smaller in cross-sectional area and, due to reduced sarcomere number, would be forced to operate over a wider range of the length-tension curve and at higher velocities, all adaptations resulting in compromised force-generating capacity. These data are relevant to physical therapy because they provide tissue-level insights into impaired muscle and shoulder function following rotator cuff injury.
Assuntos
Atrofia Muscular/fisiopatologia , Lesões do Manguito Rotador , Manguito Rotador/fisiopatologia , Adaptação Fisiológica , Análise de Variância , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Manguito Rotador/anatomia & histologia , Sarcômeros/fisiologiaRESUMO
BACKGROUND: Chronic rotator cuff tears are often associated with pain or poor function. In a rat with only a detached supraspinatus tendon, the tendon heals spontaneously which is inconsistent with how tears are believed to heal in humans. QUESTIONS/PURPOSES: We therefore asked whether a combined supraspinatus and infraspinatus detachment in the rat would fail to heal and result in a chronic injury in the supraspinatus tendon. METHODS: We acutely detached the supraspinatus and infraspinatus tendons in a rat model. At 4, 8, and 16 weeks post-detachment, biomechanical testing, collagen organization, and histological grading were evaluated for the detached supraspinatus and infraspinatus tendons and compared to controls. RESULTS: In the detached supraspinatus tendon, area and percent relaxation were increased at all time points while the modulus and stiffness were similar to those of controls at 4 and 8 weeks. Collagen disorganization increased at late time points while cellularity increased and cells were more rounded in shape. In the detached infraspinatus tendon, area and percent relaxation were also increased at late time points. However, the modulus values initially decreased followed by an increase in both modulus and stiffness at 16 weeks compared to control. In the detached infraspinatus, we also observed a decrease in collagen organization at all time points and increased cellularity and a more rounded cell shape. CONCLUSIONS: Due to the ongoing changes in mechanics, collagen organization and histology in the detached supraspinatus tendon compared to control animals at 16 weeks, this model may be useful for understanding the human chronic tendon tear. CLINICAL RELEVANCE: This rat rotator cuff chronic model can be used to test hypotheses regarding injury and repair mechanisms that cannot be addressed in human patients or in cadaveric studies.
Assuntos
Lesões do Manguito Rotador , Traumatismos dos Tendões/patologia , Cicatrização , Animais , Fenômenos Biomecânicos , Doença Crônica , Colágeno/metabolismo , Modelos Animais de Doenças , Elasticidade , Humanos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Manguito Rotador/metabolismo , Manguito Rotador/patologia , Manguito Rotador/fisiopatologia , Ruptura , Especificidade da Espécie , Traumatismos dos Tendões/metabolismo , Traumatismos dos Tendões/fisiopatologia , Fatores de TempoRESUMO
The purpose of this study was to determine the safety of tinzaparin for deep vein thrombosis prophylaxis in newly diagnosed grade III-IV malignant glioma patients. Patients were initiated on daily tinzaparin at a fixed dose of 4,500 IU subcutaneously between 48 h and 4 weeks post-operative for planned duration of 12 months. During chemotherapy cycles, blood counts were monitored weekly and tinzaparin was held if the platelet count decreased to <50,000 and was re-initiated at a platelet count >100,000. Forty patients were enrolled into the study, 35 with glioblastoma multiforme and 5 with anaplastic astrocytoma. Possible attributable toxicity was limited to two patients who developed CNS hemorrhages (one grade 1 and one grade 2) and one patient with an increase in liver enzymes (grade 3). There were no patients with a grade 4 or 5 CNS hemorrhages or systemic hemorrhages >or=grade 2. The median time on prophylactic tinzaparin was 161 days (range of 5 to 601 days). One patient developed a deep venous thrombosis while taking tinzaparin, and three patients developed thromboembolic complications while off tinzaparin. Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients.
Assuntos
Neoplasias Encefálicas/complicações , Fibrinolíticos/uso terapêutico , Glioma/complicações , Heparina de Baixo Peso Molecular/uso terapêutico , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Tinzaparina , Tomografia Computadorizada por Raios XRESUMO
HYPOTHESIS: This study examined the effect of multiple rotator cuff tendon tears on shoulder function in an animal model. MATERIALS AND METHODS: Forty-eight Sprague-Dawley rats were divided into uninjured control, supraspinatus tendon detachment, supraspinatus+infraspinatus tendon detachment, or supraspinatus+subscapularis tendon detachment groups. Functional assessment was determined through ambulatory parameters (paw and stride measures) and range of motion prior to tendon detachment and at various time points after tendon detachment. RESULTS: Ambulatory parameters and total range of motion, representing measures of shoulder function, were significantly altered with rotator cuff tears. The addition of a second torn rotator cuff tendon (infraspinatus or subscapularis)had further detrimental effects on animal shoulder function compared to uninjured control. DISCUSSION: This study demonstrated functional changes in a rat rotator cuff model. Many of the permanent functional changes were likely present because the required motion used for those actions can no longer be performed. For parameters that were transient, compensation with another limb or subsidence of pain may have occurred. CONCLUSION: The findings in this study are consistent with the alterations in shoulder function observed with rotator cuff and other shoulder injuries in the human. Future studies using this model can begin to examine the root of the functional differences, whether it is pain, mechanical deficiency, or a combination of both, which cannot be fully studied clinically [corrected].
Assuntos
Lesões do Manguito Rotador , Manguito Rotador/fisiopatologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Ratos , Ratos Sprague-DawleyRESUMO
Rotator cuff tears are disabling conditions that result in changes in joint loading and functional deficiencies. Clinically, damage to the long-head of the biceps tendon has been found in conjunction with rotator cuff tears, and this damage is thought to increase with increasing tear size. Despite its importance, controversy exists regarding the optimal treatment for the biceps. An animal model of this condition would allow for controlled studies to investigate the etiology of this problem and potential treatment strategies. We created rotator cuff tears in the rat model by detaching single (supraspinatus) and multiple (supraspinatus + infraspinatus or supraspinatus + subscapularis) rotator cuff tendons and measured the mechanical properties along the length of the long-head of the biceps tendon 4 and 8 weeks following injury. Cross-sectional area of the biceps was increased in the presence of a single rotator cuff tendon tear (by approximately 150%), with a greater increase in the presence of a multiple rotator cuff tendon tear (by up to 220%). Modulus values decreased as much as 43 and 56% with one and two tendon tears, respectively. Also, multiple tendon tear conditions involving the infraspinatus in addition to the supraspinatus affected the biceps tendon more than those involving the subscapularis and supraspinatus. Finally, biceps tendon mechanical properties worsened over time in multiple rotator cuff tendon tears. Therefore, the rat model correlates well with clinical findings of biceps tendon pathology in the presence of rotator cuff tears, and can be used to evaluate etiology and treatment modalities.
Assuntos
Lesões do Manguito Rotador , Traumatismos dos Tendões/fisiopatologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Ratos , Ratos Sprague-Dawley , Manguito Rotador/fisiopatologiaRESUMO
Although presumed, damage in the remaining (intact) rotator cuff tendons in the presence of an isolated supraspinatus tendon tear or multiple tendon tear has not been well studied. This study used an animal model of multiple rotator cuff tendon tears to investigate alterations in the remaining (intact) tendon mechanical properties at 4 and 8 weeks after injury. Twenty-four rats served as uninjured controls, whereas 72 were divided among 3 tendon detachment groups: supraspinatus tendon detachment, supraspinatus + infraspinatus tendon detachment, and supraspinatus + subscapularis tendon detachment. The remaining (intact) rotator cuff tendons had decreased mechanical properties in the presence of rotator cuff tears. The remaining (intact) subscapularis and infraspinatus tendon cross-sectional areas increased, whereas tendon modulus decreased after tears of both 1 and 2 tendons. The remaining (intact) tendon cross-sectional areas continued to increase with time after injury. These alterations could potentially lead to further tendon damage and tear progression.
Assuntos
Lesões do Manguito Rotador , Traumatismos dos Tendões/fisiopatologia , Tendões/fisiopatologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Seguimentos , Ratos , Ratos Sprague-Dawley , Manguito Rotador/fisiopatologia , Ruptura , Fatores de TempoRESUMO
Laboratory testing for heparin-induced thrombocytopenia (HIT) includes the highly sensitive, though less specific, heparin/platelet factor 4 (PF4) ELISA. A confirmatory test with excess heparin is routinely performed on positive ELISA results to improve test specificity; the significance of a negative confirmatory result is unknown. The aim was firstly to evaluate the clinical utility of the PF4 ELISA confirmatory assay, secondly to examine the relationship between ELISA optical density (OD) value and clinical diagnosis of HIT, and thirdly to assess current practice at a tertiary care medical centre regarding patients with anti-heparin/PF4 antibodies. Patients with anti-heparin/PF4 antibodies detected by commercial ELISA during 2005 were identified. A confirmatory test was performed on positive ELISA results. Patients were labeled confirmatory positive (confirm+) or confirmatory negative (confirm-). Patients were classified as HIT+ (met criteria for HIT), HIT? (HIT possible), and HIT- (did not meet criteria for HIT) utilizing ACCP guidelines. One hundred fifteen patients with anti-heparin/PF4 antibodies were identified. Ninety-eight patients were confirm+; 17 were confirm-. The majority of confirm+ patients were HIT+ or HIT?(72%); the majority of confirm- patients were HIT-(81%). Patients who were HIT+/confirm+ had higher ELISA OD values than patients who were HIT?/confirm+ or HIT-/confirm+ (p = 0.031, p = 0.001). Two confirm- patients were HIT+, one was HIT?; all had high ELISA OD values. Although confirm+ status correlated with clinical HIT, the confirmatory procedure misclassified some patients by yielding a confirm- result despite clinical HIT with high ELISA OD values. Future studies should compare higher ELISA OD values with the confirmatory procedure as strategies to improve ELISA diagnostic specificity for HIT.
Assuntos
Anticoagulantes/efeitos adversos , Ensaio de Imunoadsorção Enzimática/métodos , Heparina/efeitos adversos , Fator Plaquetário 4/imunologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Especificidade de Anticorpos , Anticoagulantes/imunologia , Autoanticorpos/sangue , Epitopos , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/imunologia , Heparina/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trombocitopenia/epidemiologia , Trombocitopenia/imunologia , Tromboembolia/tratamento farmacológico , Tromboembolia/epidemiologia , Tromboembolia/imunologiaRESUMO
Augmentation materials for rotator cuff tears, such as small intestine submucosa (SIS), have been used with the goal of improving outcome. Knowledge is limited on the use of SIS in animal models of acute and chronic rotator cuff tears. We hypothesized that the use of SIS in the surgical management of full thickness supraspinatus tears would improve histologic and biomechanical properties. Results show temporal improvements in several histologic parameters. Both acute and chronic injuries repaired with SIS have similar and increased mechanical properties respectively, compared to those repaired without SIS. In general, acute repairs with SIS were comparable to acute repairs without SIS. In chronic repairs, the use of SIS significantly reduced the cross sectional area of the healing tendon and increased the modulus. These results provide information on the use of SIS for rotator cuff repairs.
Assuntos
Mucosa Intestinal/transplante , Manguito Rotador/cirurgia , Cicatrização/fisiologia , Doença Aguda , Animais , Fenômenos Biomecânicos , Doença Crônica , Modelos Animais de Doenças , Intestino Delgado , Ratos , Ratos Sprague-Dawley , Lesões do Manguito Rotador , Transplante de Tecidos/métodosRESUMO
Low-molecular-weight heparins undergo renal elimination, and therefore the proper dosing in hemodialysis (HD) patients is unclear. It was the objective of this study to evaluate the pharmacokinetic (PK) parameters of dalteparin in patients receiving chronic HD for end-stage renal disease. We performed a multidose PK study with prophylactic doses of dalteparin in twelve HD patients. Dalteparin 5,000 IU was administered subcutaneously daily for four consecutive days, with HD performed on day 2 and day 4. Anti-factor Xa activity was determined daily and at multiple blood samples after the 3rd and 4th dose. Eleven of 12 patients completed the study. The mean (range) PK parameters determined after the 4th dose were as follows: i) maximum concentration (Cmax ) was 0.31 IU/ml (0.06 to 0.55 IU/ml); ii) time to Cmax was 3.55 hours (2.59 to 4.96 hr); iii) area under the curve was 3.24 IU*hr/ml (0.64 to 6.44 IU*hr/ml); iv) half-life was 3.82 hr (2.03 to 9.63 hr); and v) trough anti-factor Xa activity 0.04 IU/ml (0.02 to 0.08 IU/ml). No major bleeding was observed. In general, patients with lower body weight exhibited a higher Cmax . From this pilot PK study, we have determined initial PK parameters for dalteparin in HD patients. Although a standard prophylactic dose was used, we found that in this patient population differences in body weight influenced the Cmax. Future studies to evaluate the PK parameters of dalteparin in patients receiving chronic HD may have to use weight-based dosing and will need to be performed over a longer period of time.
Assuntos
Anticoagulantes/farmacocinética , Dalteparina/farmacocinética , Falência Renal Crônica/metabolismo , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/sangue , Anticoagulantes/farmacologia , Área Sob a Curva , Peso Corporal , Dalteparina/administração & dosagem , Dalteparina/sangue , Dalteparina/farmacologia , Esquema de Medicação , Monitoramento de Medicamentos , Inibidores do Fator Xa , Feminino , Humanos , Injeções Subcutâneas , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
Equine infectious anemia virus (EIAV) is a macrophage-tropic lentivirus that persistently infects horses and causes a disease that is characterized by periodic episodes of fever, thrombocytopenia, and viremia. EIAV encodes only four regulatory/accessory genes, (tat, rev, ttm, and S2) and is the least genetically complex of all known lentiviruses. We sought to determine the role of the EIAV S2 accessory gene of EIAV by introducing mutations that would prevent S2 expression on the p19/wenv17 infectious molecular clone. Virus derived from the p19/wenv17 molecular clone is highly virulent and routinely fatal when given in high doses (J. Virol. 72 (1998) 483). In contrast, an S2 deletion mutant on the p19/wenv17 background is unable to induce acute disease and plasma virus loads were reduced by 2.5 to 4.0 logs at 15 days post-infection. The S2 deleted virus failed to produce any detectable clinical signs during a 5-month observation period. These results demonstrate that S2 gene expression is essential for disease expression of EIAV.
Assuntos
Anemia Infecciosa Equina/virologia , Genes Virais , Vírus da Anemia Infecciosa Equina/patogenicidade , Proteínas Virais/genética , Sequência de Aminoácidos , Animais , Sangue/virologia , Temperatura Corporal , Linhagem Celular , Cães , Anemia Infecciosa Equina/fisiopatologia , Deleção de Genes , Genes Essenciais , Cavalos , Vírus da Anemia Infecciosa Equina/genética , Macrófagos/virologia , Mutagênese Sítio-Dirigida , DNA Polimerase Dirigida por RNA/análise , Homologia de Sequência , Carga Viral , Proteínas Virais/fisiologia , Replicação ViralRESUMO
This study examined levels of agreement and directionality of disagreement between the post-treatment self-reports of substance abuse clients and their collaterals. The study population comprised 1252 clients with a primary or secondary diagnosis of substance abuse or dependence whose treatment was publicly funded in Tennessee. Client and collateral responses to 13 questions were analyzed for levels of agreement, revealing the following: (a) levels of client-collateral agreement were high, at least 75% agreement on all 13 questions and at least 88% agreement on 10 variables; (b) a Simple Kappa Test confirmed that 11 out of 13 items had moderate to excellent nonchance agreement; (c) there was no consistent trend in directionality, that is, clients neither reported information more positively nor more negatively than their collaterals did; (d) on average, those collaterals who were spouses, parents, and children agreed more with clients compared to other types of collaterals; and (e) those collaterals who saw the clients more frequently and more recently had higher agreement than those who saw the clients less frequently. This research reaffirms that collaterals are a valuable source for verifying the accuracy of clients' self-reports and that this approach continues to hold considerable promise for substance abuse post-treatment assessment.
Assuntos
Autorrevelação , Transtornos Relacionados ao Uso de Substâncias/terapia , Revelação da Verdade , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Cooperação do PacienteRESUMO
BACKGROUND: Adult females with menorrhagia may have unrecognized mild von Willebrand's disease. Most females with known von Willebrand's disease report menorrhagia. CASE: A 38-year-old healthy female desired contraception. She described heavy menses lasting 8 days since menarche. History included uncomplicated vaginal deliveries. Physical examination was normal. The levonorgestrel intrauterine system was placed. Her menorrhagia then worsened to 14 successive days each month. Evaluation revealed mild von Willebrand's disease. At 19 months of follow-up, she retained her levonorgestrel intrauterine system and avoided pregnancy. Her menses slowly improved to spotting for 8 days each month. CONCLUSION: Von Willebrand's disease is a likely cause of menorrhagia that goes unrecognized as well as a potential cause for "failed" conservative treatment for menorrhagia. Understanding the cause of menorrhagia is an important aspect of evaluating this common symptom.
Assuntos
Dispositivos Intrauterinos Medicados/efeitos adversos , Levanogestrel/efeitos adversos , Menorragia/diagnóstico , Doenças de von Willebrand/diagnóstico , Adulto , Anticoncepção/efeitos adversos , Anticoncepção/métodos , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Levanogestrel/uso terapêutico , Menorragia/etiologia , Medição de Risco , Resultado do Tratamento , Doenças de von Willebrand/terapiaRESUMO
Shoulder overuse injuries, especially those to the supraspinatus tendon of the rotator cuff, are common musculoskeletal disorders. Unfortunately, little is known about the disease etiology and pathogenesis. The objective of this study was to determine the levels of specific inflammatory and angiogenic markers in a rat supraspinatus tendon overuse injury model. We hypothesized that inflammation would not be present early in the overuse protocol. Conversely, we hypothesized that the overuse protocol would result in increased angiogenesis early. Increases in five-lipoxygenase activating protein, cyclooxygenase-2, vascular endothelial growth factor, and von Willebrand factor were evaluated by use of reverse transcription-polymerase chain reaction from 1 day through 16 weeks of treadmill running (overuse protocol). These results provide important information on the role of angiogenesis and inflammation in the disease process. Future studies will further evaluate the mechanisms of the disease process as well as potential targeted treatment modalities.
Assuntos
Transtornos Traumáticos Cumulativos/metabolismo , Lesões do Manguito Rotador , Manguito Rotador/metabolismo , Proteínas Ativadoras de 5-Lipoxigenase , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Transtornos Traumáticos Cumulativos/complicações , Ciclo-Oxigenase 2 , Modelos Animais de Doenças , Inflamação/etiologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Neovascularização Patológica/etiologia , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandina-Endoperóxido Sintases/genética , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Fatores de Crescimento do Endotélio Vascular/biossíntese , Fatores de Crescimento do Endotélio Vascular/genética , Fator de von WillebrandRESUMO
Antiphospholipid antibodies can influence the results of clotting tests in a subset of patients, which can be a major obstacle in monitoring warfarin. The aim was to determine if point-of-care testing of the International Normalized Ratio (INR) is influenced by antiphospholipid antibodies. We compared 59 patients receiving warfarin for a diagnosis of antiphospholipid antibody syndrome (APS) to 49 patients receiving warfarin for atrial fibrillation to evaluate the consistency between INR results obtained by different methods. INR results obtained by finger stick (capillary whole-blood) and venipuncture (non-citrated and citrated whole-blood) were compared with our laboratory plasma-based prothrombin time assay. Five patients (8%) with APS and both elevated anti-beta2glycoprotein I levels and positive lupus anticoagulants had non-measurable ProTime INR results and generally higher Hemochron Signature INR results than the plasma-based method, but the corresponding chromogenic factor X results were not supratherapeutic. For the remaining patients, differences between the plasma-based INR and the point-of-care INR results ranged from 0.2 +/- 0.2 to 0.4 +/- 0.3. The differences were similar for patients with APS and atrial fibrillation for all INR comparisons with the exception of the plasma-based method compared with the ProTime, which showed a mean absolute difference of 0.4 +/- 0.3 for APS patients and of 0.2 +/- 0.2 for atrial fibrillation patients (p = 0.02). In a subset ofAPS patients, the ProTime system will not yield an INR result and the HEMochron Signature (citrate and non-citrate whole-blood) INR results will exhibit elevated INR results. For this subset of APS patients, we suggest using an alternative method to monitor warfarin.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Coeficiente Internacional Normatizado , Sistemas Automatizados de Assistência Junto ao Leito , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/tratamento farmacológico , Fibrilação Atrial/sangue , Fibrilação Atrial/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Monitoramento de Medicamentos/instrumentação , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina/instrumentação , Tempo de Protrombina/métodos , Reprodutibilidade dos Testes , Varfarina/uso terapêuticoRESUMO
Musculoskeletal soft tissue injuries from athletic activities are common in the rotator cuff tendons, lateral epicondyle of the elbow, the patella tendon, and the Achilles tendon. Despite the fact that the Achilles tendon is the largest and strongest tendon in the human body, it is frequently injured in the athletic setting. To study the etiology and pathogenesis of Achilles tendon injuries, our goal was to develop a model of Achilles tendon overuse by evaluating the Achilles tendons from animals subjected to the exercise protocol previously described as overuse for the supraspinatus tendon. We hypothesized that the same exercise protocol would produce injuries to the Achilles tendon as demonstrated by changes in the cross-sectional area and biomechanical properties. While a significant injury was induced into the supraspinatus tendon, we found no changes in the Achilles tendons of these exercised animals based on gross observation, geometric measurements, and mechanical testing analyses. Although surprising, there are many possible explanations for these findings including differences in potential injury mechanisms, functional capabilities of the differing tendons, and other factors.
Assuntos
Tendão do Calcâneo/lesões , Tendão do Calcâneo/fisiopatologia , Transtornos Traumáticos Cumulativos/fisiopatologia , Condicionamento Físico Animal/métodos , Esforço Físico , Traumatismos dos Tendões/fisiopatologia , Tendão do Calcâneo/patologia , Animais , Fenômenos Biomecânicos/métodos , Modelos Animais de Doenças , Elasticidade , Teste de Esforço/métodos , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Traumatismos dos Tendões/patologia , Resistência à Tração , ViscosidadeRESUMO
Rotator cuff tears of the shoulder are a common cause of pain and disability. The successful repair of rotator cuff tendon tears depends on the time from onset of injury to the time of surgical repair. However, the effect of time from injury to repair remains poorly understood. A rat model was used to investigate the supraspinatus tendon organizational and mechanical property changes that occur with time post-injury to understand the natural injury response in the absence of repair. It was hypothesized that increased time post-injury would result in increased detrimental changes to tendon organizational and mechanical properties. Tendons were detached at the insertion on the humerus without repair and the quantitative organizational and mechanical properties were analyzed at 1, 2, 4, 8, and 16 weeks post-detachment. Tendon detachment resulted in a dramatic decrease in mechanical properties initially followed by a progressive increase with time. The quantitative collagen fiber orientation results provided corroborating support to the mechanical property data. Based on similarities in histology and mechanical properties to rotator cuff tears in humans, the animal model presented here is promising for future investigations of the tendon's natural injury response in the absence of repair.
Assuntos
Colágeno/ultraestrutura , Manguito Rotador/patologia , Manguito Rotador/fisiopatologia , Traumatismos dos Tendões/patologia , Traumatismos dos Tendões/fisiopatologia , Cicatrização/fisiologia , Animais , Fenômenos Biomecânicos/métodos , Doença Crônica , Colágeno/metabolismo , Modelos Animais de Doenças , Elasticidade , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Lesões do Manguito Rotador , Lesões do Ombro , Articulação do Ombro/fisiopatologia , Tendões/patologia , Tendões/fisiopatologia , ViscosidadeRESUMO
A patient with antiphospholipid antibody syndrome (APS) and a history of heparin-induced thrombocytopenia required lepirudin therapy. The patient had an abnormal baseline activated partial thromboplastin time (aPTT), complicating management of his therapy. We investigated whether an alternative monitoring system, using a dry reagent technology [Thrombolytic Assessment System (TAS)], could be used to monitor the patient's whole blood ecarin clot time (ECT) and aPTT. Baseline values for the ECT and aPTT were normal with this system. During a continuous infusion of lepirudin, the patient's whole blood ECT was maintained between a desired range of 150-200 s for 73% of the time. Similarly, his whole blood aPTT was maintained between 60 and 80 s for 80% of the time. In contrast, the patient's plasma-based aPTT by standard methods was consistently > 150 s. The patient underwent surgical procedures without complications. To further investigate the finding that the patient's antibody did not affect the aPTT with this system, we performed the ECT and the aPTT assays on the TAS Analyzer with plasma samples from 10 patients with APS and abnormal aPTTs. All 10 samples had plasma ECT values within the normal range. Four patients had normalization of the aPTT, suggesting that a subset of patients with APS may benefit from the TAS aPTT assay when monitoring heparin or other anticoagulation therapy.
Assuntos
Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Proteínas Recombinantes/uso terapêutico , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Endopeptidases , Heparina/efeitos adversos , Hirudinas/administração & dosagem , Hirudinas/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Proteínas Recombinantes/administração & dosagem , Trombocitopenia/induzido quimicamente , Tempo de Coagulação do Sangue TotalRESUMO
The Tennessee Outcomes for Alcohol and Drug Services (TOADS) in collaboration with the Bureau of Alcohol and Drug Abuse Services at the Tennessee Department of Health evaluated the effectiveness of publicly funded substance abuse treatment programs in Tennessee by collecting and analyzing data from clients treated between 1998 and 2000. Using a structured questionnaire, TOADS staff conducted telephone interviews with clients 6 months after their admission to treatment facilities. The sample populations for these follow-up interviews ranged from 1,150 to 1,350 clients over the 3 years, and each year, post-treatment abstinence rates were around 60%, which suggests that treatment in Tennessee has been successful in reducing substance abuse. In addition, the follow-up interview data suggest that treatment also helped drastically reduce both unemployment and arrests among clients. These findings in Tennessee are comparable to treatment outcomes in other states. In addition to the positive effects that treatment has on clients, treatment is also cost-effective for state budgets since treatment reduces many of the burdens substance abuse places on the criminal justice system, the healthcare system, and other state-supported services.