GABAergic drug use and global, cognitive, and motor functional outcomes after stroke.

BACKGROUND: In animal models and healthy volunteers, the use of GABA A receptor agonists (GABA-AGs) seem deleterious for functional recovery. The agents are widely used for subacute stroke, but their effect on functional recovery remains unclear. OBJECTIVES: We aimed to evaluate the association between GABA-AG use and functional recovery after stroke. METHODS: We retrospectively recruited 434 survivors of subacute stroke admitted for inpatient rehabilitation between 2000 and 2013 in our institution (107 with and 327 without GABA-AG use). We used multivariate regression to assess the association of GABA-AG use and successful functional recovery, defined as reaching, between admission and discharge, the minimal clinically important difference (MCID) of 22 points on the global Functional Independence Measure (FIM). Secondary analyses were the associations of GABA-AG with cognitive and motor FIM MCID and constant GABA-AG exposure (24h/24 GABA-AG) with global, cognitive and motor FIM MCID. A new estimation of the MCID was performed with the standard error of measurement. RESULTS: Reaching the global FIM MCID was associated with GABA-AG use (adjusted odds ratio [aOR] 0.54 [95% CI 0.31-0.91], P=0.02) as well as 24h/24 GABA-AG use (aOR 0.25 [0.08-0.83]; P=0.02). Furthermore, GABA-AG and 24h/24 GABA-AG use was inversely but not always significantly associated with reaching the cognitive FIM MCID (aOR 0.56, P=0.07; aOR 0.26, P=0.06, respectively) and motor FIM MCID (aOR 0.51, P=0.07; aOR 0.13, P=0.01, respectively). The estimated MCID was 19 for global FIM, 4 for cognitive FIM, and 16 for motor FIM. CONCLUSIONS: GABA-AG use is associated with not reaching successful functional recovery during stroke rehabilitation. Randomised trials are needed to formally establish the potential deleterious effect of GABA-AG use on functional recovery.

Intracellular Ca²âº and not the extracellular matrix determines surface dynamics of AMPA-type glutamate receptors on aspiny neurons.

The perisynaptic extracellular matrix (ECM) contributes to the control of the lateral mobility of AMPA-type glutamate receptors (AMPARs) at spine synapses of principal hippocampal neurons. Here, we have studied the effect of the ECM on the lateral mobility of AMPARs at shaft synapses of aspiny interneurons. Single particle tracking experiments revealed that the removal of the hyaluronan-based ECM with hyaluronidase does not affect lateral receptor mobility on the timescale of seconds. Similarly, cross-linking with specific antibodies against the extracellular domain of the GluA1 receptor subunit, which affects lateral receptor mobility on spiny neurons, does not influence receptor mobility on aspiny neurons. AMPARs on aspiny interneurons are characterized by strong inward rectification indicating a significant fraction of Ca(2+)-permeable receptors. Therefore, we tested whether Ca(2+) controls AMPAR mobility in these neurons. Application of the membrane-permeable Ca(2+) chelator BAPTA-AM significantly increased the lateral mobility of GluA1-containing synaptic and extrasynaptic receptors. These data indicate that the perisynaptic ECM affects the lateral mobility differently on spiny and aspiny neurons. Although ECM structures on interneurons appear much more prominent, their influence on AMPAR mobility seems to be negligible at short timescales.

Life cycle assessment part 1: framework, goal and scope definition, inventory analysis, and applications.

Sustainable development requires methods and tools to measure and compare the environmental impacts of human activities for the provision of goods and services (both of which are summarized under the term "products"). Environmental impacts include those from emissions into the environment and through the consumption of resources, as well as other interventions (e.g., land use) associated with providing products that occur when extracting resources, producing materials, manufacturing the products, during consumption/use, and at the products' end-of-life (collection/sorting, reuse, recycling, waste disposal). These emissions and consumptions contribute to a wide range of impacts, such as climate change, stratospheric ozone depletion, tropospheric ozone (smog) creation, eutrophication, acidification, toxicological stress on human health and ecosystems, the depletion of resources, water use, land use, and noise-among others. A clear need, therefore, exists to be proactive and to provide complimentary insights, apart from current regulatory practices, to help reduce such impacts. Practitioners and researchers from many domains come together in life cycle assessment (LCA) to calculate indicators of the aforementioned potential environmental impacts that are linked to products-supporting the identification of opportunities for pollution prevention and reductions in resource consumption while taking the entire product life cycle into consideration. This paper, part 1 in a series of two, introduces the LCA framework and procedure, outlines how to define and model a product's life cycle, and provides an overview of available methods and tools for tabulating and compiling associated emissions and resource consumption data in a life cycle inventory (LCI). It also discusses the application of LCA in industry and policy making. The second paper, by Pennington et al. (Environ. Int. 2003, in press), highlights the key features, summarises available approaches, and outlines the key challenges of assessing the aforementioned inventory data in terms of contributions to environmental impacts (life cycle impact assessment, LCIA).

Calsyntenin-1, a proteolytically processed postsynaptic membrane protein with a cytoplasmic calcium-binding domain.

In a screen for proteins released from synapse-forming spinal cord neurons, we found the proteolytically cleaved N-terminal fragment of a transmembrane protein localized in the postsynaptic membrane of both excitatory and inhibitory synapses. We termed this protein calsyntenin-1, because it binds synaptic Ca2+ with its cytoplasmic domain. By binding Ca2+, calsyntenin-1 may modulate Ca2+-mediated postsynaptic signals. Proteolytic cleavage of calsyntenin-1 in its extracellular moiety generates a transmembrane stump that is internalized and accumulated in the spine apparatus of spine synapses. Therefore, the synaptic Ca2+ modulation by calsyntenin-1 may be subject to regulation by extracellular proteolysis in the synaptic cleft. Thus, calsyntenin-1 may link extracellular proteolysis in the synaptic cleft and postsynaptic Ca2+ signaling.

Percutaneous endoscopic gastrostomy in neurological rehabilitation: a report of six cases.

PURPOSE: This study reports the cases of six patients with severe chronic neurological disability and swallowing difficulties due to traumatic brain injury (TBI), anoxia and multiple sclerosis (MS). METHOD: The patients required nutritional supplement through percutaneous endoscopic gastrostomy (PEG). RESULTS: Their clinical follow-up showed a decrease of intercurrent medical complications, especially pressure sores. In addition, an improvement of oropharyngeal function was observed in some patients, also accompanied by slightly better basic psychomotor functions such as vigilance, sustained attention and tone or motor control. However, not every patient did improve with this procedure. The two MS patients benefited most, while the improvement was less homogenous in the three TBI patients. CONCLUSIONS: The advantages of PEG over nasogastric tube on oropharyngeal function can be related to the absence of pharyngeal irritation and its role in overall recovery could be due to an increase in social activities, a control of infections, a better rehabilitation schedule and a long-term effect on brain function due to better nutritional support.

Effect of training on muscle strength and motor function in the elderly.

Overall muscle strength and mass decline 30-50% between the ages of 30 and 80. The loss of muscle mass, the so called sarcopenia, accounts for most of the observed loss of strength. A reduced specific muscle force has also been observed but its contribution to the decrease in strength with age remains unclear. The loss of muscle tissue is due to a decrease in the number of muscle fibres and atrophy of the type II muscle fibres. The declining strength reduces the capacity to carry out basic activities of daily life and puts people at risk for falls and dependence. Resistive strength training greatly increases muscle strength even in very old people. It produces muscle fibre hypertrophy and improves neural factors involved in force production. The recovered strength in turn enhances the physical performance and allows a more active and independent life towards the end of the life span.

Knee flexion to extension peak torque ratios and low-back injuries in highly active individuals.

The purpose of this study was to investigate for possible relationships between knee flexion to extension peak torque ratios (F1/Ext(rat)) and low-back injuries in highly active males and females. Forty-eight male (age 25.9 +/- 4.5 years) and 41 female (age 27.3 +/- 2.6 years) competitive rowers, and 20 male (age 26.6 +/- 6.0 years) professional ballet dancers volunteered for the study. Each subject performed a test of lumbar and knee flexor flexibility, isokinetic dynamometry and completed a self-administered questionnaire. Flexibility was assessed by using the sit-and-reach test. Knee flexion to extension peak torques were bilaterally monitored at the angular velocities of 1.04 and 4.19 rad x s(-1). The questionnaire was designed to obtain information regarding the number of days off action (e.g., training, competition, and rehearsals), due to low-back injuries, for the 12-month period prior to testing. Results revealed significant negative correlation coefficients between knee F1/Ext(rat), obtained at 1.04 rad x s(-1), and days off physical activity for oarsmen (r = - 0.69; p < 0.01), oarswomen (r = -0.62; p < 0.01) and male dancers (r = -0.57; p < 0.05). No such correlations were found for either knee F1/ Ext(rat) obtained at the angular velocity of 4.19 rad x s(-1) or between the sit-and-reach test results and low-back injuries. A sub-group of 22 female rowers was re-tested after a 6-8 month period, during which a special hamstring strength training programme was introduced. The main conclusions were: a) the lower the F1/Ext(rat) the greater the degree of low-back injury, b) at least in female rowers, 6-8 months of hamstring strength training can contribute to a reduction of the incidence of low-back injury, and c) isokinetic assessment of quadriceps and hamstrings obtained at lower compared to higher angular velocities is more prognostic of low back injury.

The survival of embryonic cardiomyocytes transplanted into damaged host rat myocardium.

In this study, attempts were made to replace damaged myocardium of adult rats with embryonic grafts. To this purpose pieces of embryonic ventricular myocardium were prelabelled with 4',6-diamidino-2-phenylindole and placed into a damaged area of the host myocardium. The hearts containing the grafts were then examined between 2 days and 5-7 months later. Initially the 4'-6-diamindino-2-phenylindole labelled cells were localized only at the site of grafting, but by 2-5 weeks they migrated along the ventricular surface of the heart. Nevertheless the greatest density of grafted cells was always found in the damaged area. At all time points studied, the myogenic phenotype of the 4'-6-diamindino-2-phenylindole-labelled cells was maintained, as the cells contained myosin heavy chains. In addition, immunolabelling with antibodies against cardiac gap junction proteins revealed that initially gap junctions were scattered within the transplanted tissue but with time they became more organised, firstly by alignment into rows along the developing myofibres and then into structures that resembled intercalated discs. Thus the grafted embryonic cardiac myocytes survived in an adult host myocardium and expressed characteristics typical of heart cells.

A simple method for cardiac surgery in rats.

In our laboratory we have developed a relatively simple method for cardiac surgery in rats. The operation is carried out through a small incision in the chest wall using inexpensive equipment. This method allows for the delivery of tissue fragments and cells from a donor rat to an intact or damaged area of ventricular myocardium of a host rat, with easy subsequent localisation of the transplanted/grafted tissue. The rats recover well after the surgery and survive for long periods of time. The technique could also be used for the direct injection of chemicals or molecular probes into the heart. In our experiments we have found that embryonic rat cardiomyocytes that have been transplanted into adult host rat ventricular myocardium using this method survive and develop characteristics typical of heart muscle, thus indicating that using this technique the host heart offers a favourable environment for the transplanted embryonic heart cells.

The response of adult and developing rat plantaris muscle to overload.

The effect of overload on the rat plantaris muscle was studied in animals of different ages. Overload was induced by removal of gastrocnemius and soleus muscles. As expected, when the operation was carried out in adults, the plantaris muscle became heavier and stronger. These changes occured within 30 days after the operation. In animals in which the operation was carried out 1-12 days after birth and the muscle examined 6-20 weeks later, different results were obtained. In the group operated at 1-9 days of age, the muscles developed a lower maximal twitch and tetanic tension than the contralateral plantaris muscle. There was no difference in the time to peak or muscle weight between the overloaded and the contralateral muscles. Similar changes were observed in animals where the overload was induced at 11 or 12 days of age except for the weight which was significantly higher than that of the control plantaris muscles. The number of slow fibers increased in animals where overload was induced 11-12 days postnatally or in adults, but not when muscles were overloaded at 9 days of age. The possible reasons for the different response of adult and neonatal muscles to overload are discussed.

Survival of embryonic cardiac myocytes transplanted into host rat soleus muscle.

Small fragments of embryonic hearts were transplanted either alongside or into a skeletal muscle (soleus) of an adult host. The implanted tissue grew, and survived for at least 6 months after transplantation. The graft was well vascularized and established a network of blood vessels that communicated with the host's circulation. This communication appeared to be established by the proliferation of blood vessels from the graft into the host tissues. The grafted tissue was rhythmically active and the rate of these contractions was similar to that of adult rat hearts. The frequency of the spontaneous contractions could be modified by acetylcholine. Exposure to acetylcholine lead to a reversible slowing of the rate of beating. The presence of gap junctions in the transplanted tissue was revealed by visualizing connexin 43 with a specific antibody. During early periods after grafting the gap junctions were scattered within the graft but over time they became aligned into rows, to prepare for the formation of intercalated discs. Thus embryonic heart grafted into, or alongside skeletal muscle is able to acquire a considerable degree of differentiation.

Maximal voluntary quadriceps strength patterns in Olympic overtrained athletes.

Peak torques were studied in 10 elite male overtrained athletes and 10 controls matched for sex, age, sport, and performance level. Isokinetic concentric (CON) and eccentric (ECC) maximal voluntary contractions (MVC) of quadriceps muscle were assessed at the angular velocities of 60 degrees, 120 degrees, and 180 degrees.s-1. Sustained isometric MVCs were also measured at knee angles of 10 degrees, 45 degrees, and 80 degrees of flexion. Six seconds after the beginning of each isometric MVC, a 40-Hz electrical stimulation was superimposed on the MVC for a further 6 s. The overtrained subjects developed significantly smaller CON peak torques at 180 degrees.s-1 (P < 0.001), although ECC torques were similar at all three velocities. ECC/CON ratios were higher in the overtrained subjects at 120 degrees.s-1 (P < 0.01) and 180 degrees.s-1 (P < 0.001) compared with the controls. Isometric MVCs at 10 degrees and 45 degrees knee flexion were lower in the overtrained at P < 0.01 and P < 0.05, respectively. Also in the overtrained subjects, at knee angle of 10 degrees, the addition of the electrical stimulation to the isometric MVC produced an increase (P < 0.05) in torque levels. It is suggested that impaired central drive may account for the present findings.

Adaptation of rat extensor digitorum longus to overload and increased activity.

Rat extensor digitorum longus (EDL) muscles were overloaded by removal of the synergist tibialis anterior (TA). The weight of the overloaded muscle was increased 15 days after the initial operation and remained higher throughout the period studied (153 days). The times to peak twitch tension and half relaxation remained unaltered, but the twitch and tetanic tensions developed by the overloaded EDL muscles increased. The overloaded EDL muscles became significantly more fatigue resistant. In a separate group of animals the overloaded EDL muscle was also chronically stimulated at 10 Hz. The additional stimulation altered the response of the EDL to overload in that the time to peak twitch tension of the muscle was slightly prolonged. There was no increase in twitch or tetanic tension in spite of the increase in muscle weight, but the electrical stimulation led to a further increase in fatigue resistance above that seen in overloaded muscles. The histochemical and immunocytochemical examination of the muscle revealed that there was a moderate increase in succinate dehydrogenase activity in the muscles overloaded only, but a considerable increase in those overloaded muscles that were also stimulated. There was no obvious change in the number of muscle fibres that reacted with an antibody to slow myosin in either overloaded only or overloaded and stimulated EDL muscles. Thus the addition of continuous activity to overload induced a slowing of contraction and prevented the increase of force usually induced by overload.

Influence of theophylline on the electrical potential difference and ion fluxes (Na, Cl, K) across the isolated rumen epithelium of sheep.

Although it is well established that Na and Cl are actively absorbed by the rumen epithelium, nothing is known about the regulation of electrolyte transport across the rumen mucosa. Therefore, we have investigated the influence of theophylline, a known inhibitor of the enzyme phosphodiesterase, on the electrical parameters of the rumen epithelium as well as on electrolyte (Na, Cl, K) transport across this tissue. The experiments were performed using isolated rumen mucosa from sheep mounted in a Ussing type chamber. Serosal addition of theophylline resulted in a significant drop of the transepithelial potential difference as well as the short circuit current. The effect of theophylline is probably mediated by cAMP, since the addition of cAMP yielded qualitatively similar results. With respect to the ion fluxes only transport of Na in the muco-serosal direction and as a result the net flux of Na were significantly reduced in the presence of theophylline. The effects of theophylline on rumen epithelium are best explained by an inhibition of electrogenic as well as electroneutral Na transport. Since cAMP serves as a second messenger for the effect of various regulatory substances including gastrointestinal hormones and transmitters regulation of electrolyte transport across the rumen epithelium possibly occurs under physiological conditions.

Adenosine increases an internal calcium store in the smooth muscle of guinea-pig taenia coli.

The effect of adenosine on an internal calcium store which can be released by carbachol to produce a transient contraction in Ca2+-free solution was investigated in the taenia depolarized by high K+. The carbachol contraction in Ca2+-free solution was increased by the preceding application of adenosine (3 X 10(-5) to 10(-3) M), an effect which was mimicked by ATP, but not by the slowly degradable analog alpha, beta-methylene ATP. The P1-purinoceptor antagonist 8-phenyltheophylline inhibited the increase caused by adenosine without modifying the carbachol contraction in controls. It is concluded that stimulation of an extracellular P1-purinoceptor increases an internal store of calcium, which might contribute to the relaxation induced by adenosine in the taenia.

Calcium movements and the mechanism of the relaxation induced by adenosine in the guinea-pig taenia coli.

The effects of adenosine on the calcium contraction of high K+ (low Na+)-depolarized preparations, as well as on the uptake and release of 45Ca, were studied in the guinea-pig taenia coli. Adenosine (10(-4)-10(-3) M) inhibited the calcium contraction of high K+-depolarized preparations, an effect which was mimicked by ATP (10(-4)-10(-3) M), but not by the slowly degradable ATP analog, adenosine 5'-alpha, beta-methylene triphosphate. The high K+ -stimulated calcium influx measured by 3-6 min exposures to 45Ca was not changed by adenosine (10(-3) M). In high K+ solution, adenosine (10(-3) M) increased the fractional rate of efflux of 45Ca-labelled preparations. These results indicate that stimulation of calcium extrusion, but not inhibition of calcium influx, may take part in the mechanism of the relaxation induced by adenosine in the taenia.