Increased vulnerability to demyelination in streptozotocin diabetic rats

Demyelination is a prominent feature in nerve biopsies of patients with diabetic neuropathy. The mechanism is unknown because diabetic rodents, unlike humans, do not consistently develop segmental demyelination. We examined how diabetes influences toxicant-induced demyelination, remyelination, Schwann cell nerve growth factor receptor (p75) expression, and endoneurial macrophage apolipoprotein E (apo E) synthesis in diabetic rats. Postnatal day 17 (P17) rats were given 110 mg/kg streptozotocin intraperitoneally and then fed a diet containing metallic tellurium (Te) from P20 to P27 to induce demyelination. Transverse electron micrographs and immunostained longitudinal cryosections were prepared from sciatic nerve during demyelination and remyelination. Diabetic rats had a mean serum glucose concentration of 490 mg/dl and consumed equivalent doses of peroral Te. The number of demyelinated fibers in electron micrographs was increased significantly by 17% (P < .0011). Endoneurial density of p75-stained Schwann cells was increased in diabetic rats in proportion to the increased number of injured internodes. Density of apo E- and ED1-positive macrophages also was significantly increased in diabetes. There was no delay in macrophage myelin clearance, and remyelination was not compromised. Increased Schwann cell vulnerability to stress, by increasing the turnover rate of myelinated units, may explain why myelin defects accumulate after long-standing diabetes. © 1996 Wiley-Liss, Inc.     

Reduced oxidative muscle metabolism in chronic fatigue syndrome

The purpose of this study was to determine if chronic fatigue syndrome (CSF) is characterized by abnormalities in oxidative muscle metabolism. Patients with CFS according to Centers for Disease Control (CDC) criteria (n = 22) were compared to normal sedentary subjects (n = 15). CFS patients were also tested before and 2 days after a maximal treadmill test. Muscle oxidative capacity was measured as the maximal rate of postexercise phosphocreatine (PCr) resynthesis using the ADP model (V_max) in the calf muscles using ³¹P magnetic resonance spectroscopy. V_max was significantly reduced in CFS patients (39.6 ± 2.8 mmol/L/min, mean ± SE) compared to controls (53.8 ± 2.8 mmol/L/min). Two days postexercise there was no change in resting inorganic phosphate (Pi)/PCr or V_max in the CFS patients (n = 14). In conclusion, oxidative metabolism is reduced in CFS patients compared to sedentary controls. In addition, a single bout of strenuous exercise did not cause a further reduction in oxidative metabolism, or alter resting Pi/PCr ratios. © 1996 John Wiley & Sons, Inc.     

CLINICAL SPASTICITY ASSESSMENT USING THE MODIFIED TARDIEU SCALE DOES NOT REFLECT JOINT ANGULAR VELOCITY OR RANGE OF MOTION DURING WALKING: ASSESSMENT TOOL IMPLICATIONS

ObjectiveSpasticity assessment is often used to guide treatment decision-making. Assessment tool limitations may influence the conflicting evidence surrounding the relationship between spasticity and walking. This study investigated whether testing speeds and joint angles during a Modified Tardieu assessment matched lower-limb angular velocity and range of motion during walking.DesignObservational study.SubjectsThirty-five adults with a neurological condition and 34 assessors.MethodsThe Modified Tardieu Scale was completed. Joint angles and peak testing speed during V3 (fast) trials were compared with the same variables during walking in healthy people, at 0.40–0.59, 0.60–0.79 and 1.40–1.60 m/s. The proportion of trials in which the testing speed, start angle, and angle of muscle reaction matched the relevant joint angles and angular velocity during walking were analysed.ResultsThe Modified Tardieu Scale was completed faster than the angular velocities seen during walking in 88.7% (0.40–0.59 m/s), 78.9% (0.60– 0.79 m/s) and 56.2% (1.40–1.60 m/s) of trials. When compared with the normative dataset, 4.2%, 9.5% and 13.7% of the trials met all criteria for each respective walking speed.ConclusionWhen applied according to the standardized procedure and compared with joint angular velocity during walking, clinicians performed the Modified Tardieu Scale too quickly.LAY ABSTRACTSpasticity is an abnormal increase in muscle tightness, which is common following neurological injury. Spasticity has been shown to have a profound impact on an individual’s independence and quality of life. The main goal reported by patients in this population is to return to independent, normal walking. Yet, despite this there is a lack of consensus regarding the relationship between spasticity and walking outcomes. This may be due to a disconnect between clinical, bed-based assessment methods and how spasticity manifests during walking. This study aimed to establish how well a routine clinical assessment (the Modified Tardieu Scale) matched the speed and range of joint movement during walking. The findings suggest that, currently, clinicians performed the assessment too fast, which may lead to “false-positive” assessment findings. This may result in the identification and treatment of spasticity that is not impacting walking, leading to sub-optimal patient outcomes and significant healthcare wastage.Key words: muscle spasticity, patient outcome assessment, rehabilitation, brain injuries, gait, walking

Spasticity is a common impairment following neurological injury (1–5). The effective assessment and management of spasticity receives significant attention due to the detrimental effects it has on patient outcomes, carer burden, and quality of life (6, 7). Current spasticity guidelines recommend that only spasticity impacting function should receive intervention (8). As such, the role of a clinical assessment is to identify the presence of spasticity and decipher whether the spasticity warrants intervention, such as botulinum toxin-A (BoNT-A).Walking limitations are the most significant selfperceived, functional problem reported by individuals following neurological injury (9). A primary rehabilitation goal is often to improve walking independence, quality, speed, and endurance (10–12). In relation to spasticity, the clinician’s role is to identify whether spasticity is present, and subsequently determine if a patient’s walking may benefit from spasticity-related interventions.A definition of spasticity published by Pandyan et al. (13); “disordered sensori-motor control, resulting from an upper motor neurone lesion, presenting as intermittent or sustained involuntary activation of muscles’’, encompasses all the positive features of upper motor neurone syndrome (UMNS) under an umbrella term of spasticity. This terminology defines spasticity as a broader sensori-motor phenomenon (13), when compared with the more constrained, velocity-dependent definition published by Lance (14);”a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflexes, as one component of the UMNS” (14). For the purpose of this study, Lance’s definition has been used to define spasticity, since, with this definition, spasticity can be assessed as an individual construct. The Modified Tardieu Scale (MTS) is an often-recommended spasticity assessment, aligning with Lance’s (14) definition of spasticity (15–17). The MTS classifies the response of a relaxed muscle to a fast, passive stretch (V3). The assessment protocol involves a clinician moving the joint “as fast as possible” through its full range of motion (ROM) without specifying or measuring the speed of completion. The MTS is applied according to this standardized protocol regardless of the functional status or goals of the patient. For example, a household ambulator walking at ≤ 0.30 m/s is assessed at the same speed as a community ambulator walking at ≥ 0.80 m/s, whose muscles and joints are moving much faster when walking (18). This “one-size-fits” all approach does not take into account the variability in joint ROM and angular velocity (or speed of lowerlimb movement) with changes in walking speed (19). As such, the MTS may not sensitively discriminate individuals who have spasticity impacting their walking.While it is well established that interventions, such as BoNT-A, reduce spasticity at an impairment-based level, current treatment modalities for spasticity do not necessarily lead to improved walking outcomes (20–22). This may be because standardized protocols for scales such as the MTS do not reflect joint movement during walking (23–25). For example, if clinicians test at a speed that is slower than the joint angular velocity seen during walking, they may fail to identify spasticity that is affecting walking (i.e. false-negative). Conversely, if clinicians test at a speed that exceeds the joint angular velocity seen during walking, they may identify spasticity that is not impacting walking (i.e. false-positive).Matching the joint angles and testing speed of the MTS to the ROM and angular velocity seen during walking may assist in identifying patients who have spasticity impacting functional performance, leading to treatment decisions that optimize patient outcomes and healthcare resources. This study aimed to compare the joint start angle, angle of muscle reaction, and testing speed during a standardized MTS assessment of 4 major muscle groups of the lower-limb, collected in people with neurological conditions, with joint ROM and angular velocity in a healthy population walking at a range of speeds.     

Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies

Apalutamide, an androgen receptor signaling inhibitor, in combination with androgen-deprivation therapy (ADT), is approved for treatment of patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer, based on the data from the phase 3 SPARTAN and TITAN studies respectively. Apalutamide is an inducer of cytochrome P450 enzymes and P-glycoprotein, which are involved in the metabolism of oral anticoagulants (OACs) and may thus have potential drug-drug interactions when co-administered with OACs. Concomitant use of certain OACs such as apixaban, rivaroxaban, edoxaban, dabigatran, and warfarin was allowed in the SPARTAN and TITAN studies. A post-hoc analysis was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic adverse events (AEs) in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT in both the studies. Anticoagulants were identified by WHO Drug Anatomical Therapeutic Chemical level 4 classifications. Thrombotic and embolic AEs were coded using the Medical Dictionary for Regulatory Activities Version 22.1. Data were analyzed from patients receiving concurrent OACs among all treated patients in SPARTAN (apalutamide + ADT: 95/803 [11.8%]; placebo + ADT: 48/398 [12.1%]) and TITAN (apalutamide + ADT: 31/524 [5.9%]; placebo + ADT: 28/527 [5.3%]). No consequential differences were observed in the occurrence of thrombotic and embolic events between apalutamide + ADT and placebo + ADT groups receiving concomitant OACs in SPARTAN (11.6% vs 12.5%) or TITAN (19.4% vs 21.4%). Grade 3/4 thrombotic and embolic AEs observed in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT were 6 (6.3%) vs 5 (10.4%) in SPARTAN and 3 (9.7%) vs 1 (3.6%) in TITAN. This analysis suggests that when necessary, concomitant OACs can be used with apalutamide with appropriate monitoring.     

Therapeutic levels of short-term tramadol administration negatively affect testis function in rats

Objective:To investigate the effects of 30-day treatment with therapeutic dose equivalent levels of tramadol on serum testosterone level, sperm parameters, and ...