How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

Modulation of rat brain synaptosomal plasma membrane achieved by atracurium and its metabolite laudanosine

Objective: Atracurium besylate and laudanosine cause excitement and seizures when introduced into the central nervous system of laboratory animals. We examined the modulation of lipid-protein interaction in the lipid environment of rat brain synaptosomal plasma membrane (SPM)-bound enzymes as a possible mechanism leading to these effects. Methods: The effect of various concentrations of atracurium besylate and laudanosine, or of varying duration of SPM, on the activity of Na(+)/K(+) stimulated ATPase, Mg(2+)-stimulated ATPase and 5’-nucleotidase were assessed. The modulation of lipid protein interaction by laudanosine was estimated on the basis of the temperature dependence and cooperative behaviour of Na(+)/K(+) stimulated ATPase. Results: The effect of atracurium besylate or laudanosine on Na(+)/K(+)-stimulated ATPase activity was biphasic. Maximal enzyme stimulation appeared at 10(-4) M atracurium besylate or 10(-8) M laudanosine, and at 30 min of pre-incubation with both drugs, Arrhenius plots of Na(+)/K(+)-stimulated ATPase showed a transition temperature of 23.0 +/- 1.2 degrees C in control SPM and shifted to 16.5 +/- 0.9 degrees C (p < 0.01) in SPM treated with 10(-8) M laudanosine, The Hill coefficients for the allosteric inhibition of Na(+)/K(+)-stimulated ATPase by fluoride decreased from 1.99 +/- 0.22 in controls to 1.06 +/- 0.11 (p < 0.001) in the presence of 10(-8) M laudanosine. Conclusions: Our results suggest that laudanosine, one of the principal metabolites of atracurium besylate, affects nerve cell function in rats through the perturbation of the membrane lipid structure accompanied by SPM-bound enzyme dysfunction

Modulation of synaptosomal plasma membrane-bound enzyme activity through the perturbation of plasma membrane lipid structure by bupivacaine

We investigated modulations of lipid dynamics and lipid-protein interactions of rat brain synaptosomal plasma membrane (SPM) as one of the possible mechanisms by which the local anesthetic bupivacaine (BPV) has an adverse effect on nerve cell function, with SPM-bound enzyme activity used as a functional probe. The kinetics of BPV impact on the activity of the endoenzymes Ca2+/Mg2+-stimulated ATPase and Na+/K+-stimulated ATPase and the active concentrations of the drug were relevant to those that produce biphasic systemic toxicity. Arrhenius plots of these enzymes showed a transition temperature of 26.6 +/- 1.8 degrees C and 24.5 +/- 1.2 degrees C (mean +/- SD), respectively, in control SPM, which shifted to 17.1 +/- 0.95 degrees C (P < 0.01) and 18.2 +/- 0.85 degrees C (P < 0.05) in SPM treated with 10(-5) M BPV. The Hill coefficients for the allosteric inhibition of Ca2+/Mg2+-stimulated ATPase by Na+ and Na+/K+-stimulated ATPase by fluoride decreased from 1.73 +/- 0.20 and 1.95 +/- 0.25, respectively, in controls to 0.92 +/- 0.09 (P < 0.001) and 1.09 +/- 0.11 (P < 0.001) in the presence of 10(-5) M BPV. The fluidity perturbation in the microenvironment of the ectoenzyme acetylcholinesterase was observed only at 5 X 10(-3) M BPV, as confirmed by the disparity in transition temperature between the controls (22.3 +/- 1.2 degrees C) and the BPV-treated SPM (17.5 +/- 0.8 degrees C, P < 0.01) and that in the Hill coefficient in the two groups: 2.15 +/- 0.24 and 0.97 +/- 0.12 (P < 0.001), respectively. Implications: We propose that under physiological conditions, the neutral and protonated forms of local anesthetics can affect nerve cell function through the asymmetric perturbation of the membrane lipid structure, accompanied by synaptosomal plasma membrane-bound enzyme dysfunction

Imbalance of tissue-type plasminogen activator (t-PA) and its specific inhibitor (PAI-1) in patients with rheumatoid arthritis associated with disease activity

The relationship between plasma fibrinogen, D-dimer (DD), t-PA and PAI-1 and their correlation with disease activity (DA) were studied in 45 patients with rheumatoid arthritis (RA) (group B) to further understand the implication of fibrinolysis in the pathophysiology of RA, The control group constituted 24 healthy subjects (group A). A Stoke index (SI) of DA was assigned to each patient, Patients were divided into two groups: C, minimal-mild DA (SI 1-7); D, moderate-severe DA (SI 8-17), Fibrinogen was elevated in RA correlating positively with SI and CRP, Hypercoagulability counteracted by reactive fibrinolysis was inferred from a 10-fold increase of DD in group B as compared to group A. The relatively lower levels of DD in group D compared to group C and their negative correlation with SI (r(s)=-0.49, p=0.0006) indicate the tendency of fibrinolysis to decrease with the increase of DA. Significant elevation of t-PA and PAI-1 were found in group B compared to group A, While t-PA progressively decreased with the increase of DA (r(s)=-0.45, p=0.0019), a positive relation of PAI-1 to DA was observed (r(s)=0.42, p=0.0042). A 2-fold increase of PAI-1/t-PA molar ratio in group D compared to groups A and C as well as its positive correlation with SI (r(s)=0.63, p=0.0001) indicate the displacement of balance between t-PA and PAI-1 in favour of the inhibitor with the increase of DA in RA. The involvement of inflammatory mediators in PAI-1/t-PA imbalance was proposed from the relation of fibrinolytic abnormalities with the activity of systemic inflammatory process

Plasma tetranectin levels in patients with unstable and stable angina

It has been recently suggested that the acute exacerbation of chronic inflammatory process accompanied by excessive atheromatous plaque-matrix breakdown may be the crucial link between chronic and acute coronary artery disease (CAD). In the light of this probability, the fibrinolytic regulator, tetranectin (TN) was assessed in the plasma of 43 unstable angina (UA) patients, 35 stable angina (SA) patients, and 34 healthy subjects (HS) in association with selected inflammatory and fibrinolytic markers. Plasma TN levels in patients with UA and SA were significantly lower than those in HS (8.18 (7.08-9.58) mg/L and 10.00 (7.22-10.96) mg/L vs 12.09 (11.78-12.37) mg/L, Er < 10(-4)). The sensitivity, specificity and predictive value were 72.1, 97.1 and 97% respectively for UA patients, and 46, 97 and 94% respectively for SA patients. In the 26 (60.5%) of UA patients, which had a complicated in-hospital course, TN levels were significantly lower than those in the 17 (39.5%) uncomplicated UA patients (7.38 (6.77-8.15) mg/L vs 9.67 (8.47-10.84) mg/L, p < 10(-4)). In SA patients the increased levels of C-reactive protein (CRP), fibrinogen (FG), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-I) and D-dimer (DD), in conjunction with the significant positive correlation between CRP and FG, and of both with DD, revealed the existence of a low-grade inflammatory process accompanied by the subclinical activation of reactive fibrinolysis. The substantial increase in the above-mentioned inflammatory and haemostatic markers, along with the significant correlation between the inflammatory markers and DD, as well as between t-PA and DD or FG in UA patients, was consistent with the acceleration of inflammatory and coagulative/fibrinolytic processes. The negative correlation of TN with CRP (r(s) = -0.707, p < 10(-3)) and FG (r(s) = -0.664, p < 10(-4)) in UA patients and, to a lesser degree, in SA patients (r(s) = -0.563, p < 10(-3) and r(s) = -0.457; p = 0.006 respectively) makes possible the involvement of inflammatory components in the regulation of TN in CAD. The negative correlation of TN with DD in SA (r(s) = -0.356, p = 0.036) and UA (r(s) = -0.319, p = 0.037) patients along with its superior performance characteristics and predictive correlation with UA clinical outcome in comparison with other inflammatory and fibrinolytic variables studied, suggested its possible implication in the pathophysiologically-important processes associated with atheromatous plaque-matrix breakdown and thrombus dissolution. The significant inverse relation between TN and lipoprotein (a) [Lp(a)] observed in SA (r(s) = -0.552, p = 0.001) hinted at the common implication of these fibrinolytic regulators in the pathophysiology of chronic CAD. A further investigation of the role played by TN in CAD could perhaps shed light on its significance as a marker of the development of coronary atheromatous lesions and thrombosis