Complications following spinal cord injury: occurrence and risk factors in a longitudinal study during and after inpatient rehabilitation

Objective: To assess the occurrence and risk factors for complications following spinal cord injury during and after inpatient rehabilitation. Design: Multicentre longitudinal study. Subjects: A total of 212 persons with a spinal cord injury admitted to specialized rehabilitation centres. Methods: Assessments at the start of active rehabilitation (n = 212), 3 months later (n = 143), at discharge (n = 191) and 1 year after discharge (n = 143). Results: Multi-level random coefficient analyses revealed that complications were common following spinal cord injury. Most subjects reported neurogenic and musculoskeletal pain, or had spasticity at each assessment. During the year after discharge, complications remained common: urinary tract infections and pressure sores affected 49% and 36% of the population, respectively. The degree of pain decreased, whereas the degree of spasticity increased significantly during inpatient rehabilitation. Overall, increased age, increased body mass index, traumatic lesion, tetraplegia, and complete lesion all increased the risk of complications. Conclusion: Complications are common following spinal cord injury. They need specific attention after discharge from inpatient rehabilitation and within subpopulations. © 2007 Foundation of Rehabilitation Information

Structural Evaluation of EGFR Inhibition Mechanisms for Nanobodies/VHH Domains

SummaryThe epidermal growth factor receptor (EGFR) is implicated in human cancers and is the target of several classes of therapeutic agents, including antibody-based drugs. Here, we describe X-ray crystal structures of the extracellular region of EGFR in complex with three inhibitory nanobodies, the variable domains of heavy chain only antibodies (VHH). VHH domains, the smallest natural antigen-binding modules, are readily engineered for diagnostic and therapeutic applications. All three VHH domains prevent ligand-induced EGFR activation, but use two distinct mechanisms. 7D12 sterically blocks ligand binding to EGFR in a manner similar to that of cetuximab. EgA1 and 9G8 bind an epitope near the EGFR domain II/III junction, preventing receptor conformational changes required for high-affinity ligand binding and dimerization. This epitope is accessible to the convex VHH paratope but inaccessible to the flatter paratope of monoclonal antibodies. Appreciating the modes of binding and inhibition of these VHH domains will aid in developing them for tumor imaging and/or cancer therapy

Cardiovascular disease risk in adults with spastic bilateral cerebral palsy

Objective: To explore: (i) cardiovascular disease risk factors and the 10-year clustered risk of a fatal cardiovascular event in adults with spastic bilateral cerebral palsy; and (ii) relationships between the 10-year risk and body fat, aerobic fitness and physical activity. Design: Cross-sectional study. Subjects: Forty-three adults with spastic bilateral cerebral palsy without severe cognitive impairment (mean age 36.6 years (standard deviation 6); 27 men). Methods: Biological and lifestyle-related risk factors and the 10-year risk according to the Systematic Coronary Risk Evaluation (SCORE) were assessed. Relationships were studied using multivariable linear regression analysis. Results: The following single risk factors were present: hypertension (n = 12), elevated total cholesterol (n = 3), low high-density lipoprotein cholesterol (n = 5; all men), high-risk waist circumference (n = 11), obesity (body mass index; n = 5; all men), reduced aerobic fitness (on average 80% of reference values), reduced level of everyday physical activity (on average 78% of reference values) and smoking (n=9). All participants had a 10-year risk <1%. Corrected for gender, participants with higher waist circumference (β = 0.28; p = 0.06) or body mass index (β=0.25; p = 0.08) tended to have a higher 10-year risk. Conclusion: In this relatively young adult sample of people with spastic bilateral cerebral palsy several single cardiovascular disease risk factors were present. The 10-year fatal cardiovascular disease risk was low, and higher body fat tended to be related to higher 10-year risk

Functional independence and health-related functional status following spinal cord injury: A prospective study of the association with physical capacity

Objective: To determine changes in functional independence following spinal cord injury and to evaluate the association between functional independence and physical capacity. Design: Multi-centre prospective cohort study. Subjects: Patients with spinal cord injury admitted for initial rehabilitation. Methods: The motor Functional Independence Measure (FIMmotor) was determined at the start of rehabilitation (n=176), 3 months later (n=124), at discharge (n=160) and one year after discharge from inpatient rehabilitation (n=133). One year after discharge, physical and social dimensions of health-related functional status (Sickness Impact Profile 68; SIP68) were determined. On each occasion, physical capacity was established by measuring arm muscle strength, peak power output and peak oxygen uptake. Results: Multi-level random coefficient analyses revealed that FIMmotor improved during inpatient rehabilitation, but stabilized thereafter. Changes in FIMmotor were associated with peak power output. Multiple regression models showed that FIMmotor and peak power output at discharge were associated with FIMmotor one year after discharge (R2=0.85), and that peak power output at discharge was associated with the social dimension of the SIP68 (R2=0.18) one year after discharge. Conclusion: Functional independence improves during inpatient rehabilitation, and functional independence is positively associated with peak power output

Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking

Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. KIR2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (IK1), are degraded in lysosomes. Amiodarone and dronedarone are class III antiarrhythmics. Chronic use of amiodarone, and to a lesser extent dronedarone, causes serious adverse effects to several organs and tissue types, including the heart. Both drugs have been described to interfere in the late-endosome/lysosome system. Here we defined the potential interference in KIR2.1 backward trafficking by amiodarone and dronedarone. Both drugs inhibited IK1 in isolated rabbit ventricular cardiomyocytes at supraclinical doses only. In HK-KWGF cells, both drugs dose- and time-dependently increased KIR2.1 expression (2.0 ± 0.2-fold with amiodarone: 10 μM, 24 hrs; 2.3 ± 0.3-fold with dronedarone: 5 μM, 24 hrs) and late-endosomal/lysosomal KIR2.1 accumulation. Increased KIR2.1 expression level was also observed in the presence of Nav1.5 co-expression. Augmented KIR2.1 protein levels and intracellular accumulation were also observed in COS-7, END-2, MES-1 and EPI-7 cells. Both drugs had no effect on Kv11.1 ion channel protein expression levels. Finally, amiodarone (73.3 ± 10.3% P < 0.05 at −120 mV, 5 μM) enhanced IKIR2.1 upon 24-hrs treatment, whereas dronedarone tended to increase IKIR2.1 and it did not reach significance (43.8 ± 5.5%, P = 0.26 at −120 mV; 2 μM). We conclude that chronic amiodarone, and potentially also dronedarone, treatment can result in enhanced IK1 by inhibiting KIR2.1 degradation

Physical fitness in people with a spinal cord injury: the association with complications and duration of rehabilitation.

Objective: To assess the association between physical fitness and its recovery over time on the one hand, and complications and duration of phases of rehabilitation on the other. Design and setting: Prospective cohort study at eight rehabilitation centres. Subjects: People with a spinal cord injury were assessed four times: at the start of active rehabilitation (n = 110), three months later (n = 92), at discharge (n = 137) and a year after discharge from inpatient rehabilitation (n = 91). Main measures: Physical fitness was defined as aerobic capacity, determined at each occasion by the peak oxygen uptake (peak V

Case Report: An EGFR-Targeted 4-1BB-agonistic Trimerbody Does Not Induce Hepatotoxicity in Transgenic Mice With Liver Expression of Human EGFR

Agonistic monoclonal antibodies (mAbs) targeting the co-stimulatory receptor 4-1BB are among the most effective immunotherapeutic agents across pre-clinical cancer models. However, clinical development of full-length 4-1BB agonistic mAbs, has been hampered by dose-limiting liver toxicity. We have previously developed an EGFR-targeted 4-1BB-agonistic trimerbody (1D8N/CEGa1) that induces potent anti-tumor immunity without systemic toxicity, in immunocompetent mice bearing murine colorectal carcinoma cells expressing human EGFR. Here, we study the impact of human EGFR expression on mouse liver in the toxicity profile of 1D8N/CEGa1. Systemic administration of IgG-based anti-4-1BB agonist resulted in nonspecific immune stimulation and hepatotoxicity in a liver-specific human EGFR-transgenic immunocompetent mouse, whereas in 1D8N/CEGa1-treated mice no such immune-related adverse effects were observed. Collectively, these data support the role of FcγR interactions in the major off-tumor toxicities associated with IgG-based 4-1BB agonists and further validate the safety profile of EGFR-targeted Fc-less 4-1BB-agonistic trimerbodies in systemic cancer immunotherapy protocols