Novel MECP2 gene therapy is effective in a multicenter study using two mouse models of Rett syndrome and is safe in non-human primates.

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.

Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue.

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.

Plasticity of muscle architecture after supraspinatus tears.

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.

Tendon properties remain altered in a chronic rat rotator cuff model.

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.

Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients.

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.

Alterations in function after rotator cuff tears in an animal model.

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.

After rotator cuff tears, the remaining (intact) tendons are mechanically altered.

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.

Mechanical properties of the long-head of the biceps tendon are altered in the presence of rotator cuff tears in a rat model.

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.

Anti-heparin/platelet factor 4 antibody optical density values and the confirmatory procedure in the diagnosis of heparin-induced thrombocytopenia.

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.

Use of small intestine submucosa in a rat model of acute and chronic rotator cuff tear.

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.

A multi-dose pharmacokinetic study of dalteparin in haemodialysis patients.

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.

The S2 accessory gene of equine infectious anemia virus is essential for expression of disease in ponies.

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.

Point-of-care testing of the international normalized ratio in patients with antiphospholipid antibodies.

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.

Factors associated with client-collateral agreement in substance abuse post-treatment self-reports.

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.

von Willebrand's disease diagnosed after menorrhagia worsened from levonorgestrel intrauterine system.

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.

Inflammatory and angiogenic mRNA levels are altered in a supraspinatus tendon overuse animal model.

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.

The effect of overuse activity on Achilles tendon in an animal model: a biomechanical study.

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.

Supraspinatus tendon organizational and mechanical properties in a chronic rotator cuff tear animal model.

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.

Management of lepirudin therapy for a patient with antiphospholipid antibody syndrome using the whole blood ecarin clot time and activated partial thromboplastin time.

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.

Substance abuse treatment effectiveness of publicly funded clients in Tennessee.

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.

Clinical and laboratory evaluation of thrombophilia.

Thrombophilia is the predisposition to venous thromboembolism and is caused by inherited and acquired factors, alone or in combination. With the discovery of APC resistance and the prothrombin gene mutation, more than half of all patients with clinical characteristics of thrombophilia are now diagnosed with an inherited disorder. The hypercoagulable work-up of patients with venous thromboembolism is important, because the causes can influence the duration and management of anticoagulation therapy, as well as affect other decisions regarding life and health issues.

A limited sampling strategy for pharmacokinetic directed therapy with intravenous busulfan.

High-dose busulfan is widely used in allogeneic and autologous marrow transplantation preparative regimens. Variation in the area under the concentration/time curve (AUC) for oral busulfan results in substantial risk of over or under treatment with excess risk of toxicity or relapse. Use of the IV formulation reduces this variability by eliminating variability in absorption.