Serum troponin Ic values in organ donors are related to donor myocardial dysfunction but not to graft dysfunction or rejection in the recipients.

BACKGROUND: Increased plasma cardiac troponin I (cTnI) values in heart donors are associated with donor myocardial dysfunction and increased risk of rejection in the recipients. We investigated the association between cTnI values and myocardial dysfunction in potential heart donors and the relationship between donors' cTnI values and recipients' early myocardial function and 1 year survival and risk of rejection. METHODS: cTnI was measured in 159 consecutive potential heart donors. Myocardial function was estimated by the left ventricular ejection fraction (LVEF) and segmental wall motion abnormalities (SWMA). Results are mean+/-SD (range) or median (interquartile range). RESULTS: cTnI values in potential donors were 2.1+/-5 ng/ml (0-40.4 ng/ml); cTnI values were significantly (P<0.001) higher: 4.2+/-5.9 ng/ml (0-30.6 ng/ml) for potential donors with LVEF <50% versus LVEF >50%: 1.7+/-4.7 ng/ml (0-40.4 ng/ml). cTnI values were significantly lower for donors without SWMA. cTnI values were significantly (P<0.001) lower for the 90 donors whose hearts were harvested: 1.1+/-2.3 ng/ml (0-15.6 ng/ml) versus the not harvested: 3.6+/-6.9 ng/ml (0-40.4 ng/ml). There were 87 recipients followed for 1 year. Donors' cTnI values were not associated with early alteration of LVEF, incidence of rejection or 1 year recipients' survival. CONCLUSION: Increased cTnI values in potential heart donors are statistically associated with myocardial dysfunction and could be helpful for organ selection. In contrast, cTnI values in heart donors were not associated with graft dysfunction or recipient survival after transplantation.

Relationship between procalcitonin values and infection in brain-dead organ donors.

BACKGROUND AND AIMS: An association between the inflammatory reactions estimated by several biomarkers and organ dysfunction has been reported in brain-dead organ donors (BDOD). Procalcitonin (PCT), a biomarker of inflammation due to bacterial infection, is increased among BDOD. However, is not known whether infection changes PCT values in BDOD. MATERIALS AND METHODS: We retrospectively analyzed 82 BDOD including several demographic and clinical parameters, bacterial culture results, antibiotics prescription, and plasma values of PCT measured before organ harvesting. Infection was diagnosed to be either a positive bacterial culture (restricted definition) and/or prescription of antibiotics (extended definition). RESULTS: The median PCT value was 1.5 (interquartile range [IQR], 0.4 to 6.9; range, 0 to 526 ng/mL; n=82). Thirty-eight (46%) and 24 (29%) patients had PCT values>2 ng/mL and >5 ng/mL, respectively. Median PCT values among infected (1.18; IQR, 0.27 to 6.55 ng/mL) versus noninfected (1.57; IQR, 0.53 to 7.15 ng/mL) BDOD (restricted definition) were not different (P=.36). The area under the receiver operating characteristic curve using PCT to predict infection (restricted definition) was 0.52. Specificity of PCT to predict infection was above 80% at PCT values>9 ng/mL. CONCLUSION: Our results confirmed PCT values are increased in BDOD, suggesting that this was not related to an infectious cause (whatever definition was used) unless PCT values are high.

Sequential measurements of troponin Ic values in brain-dead patients considered as potential heart donors.

It was suggested that a single value of normal or increased plasma cardiac troponin T or I (cTnT or cTnI) concentration could contribute to estimate donor myocardial damage and function in brain-dead patients. In patients with acute coronary syndromes, an initial normal value of troponin must be confirmed several hours later but no such recommendations exist for brain-dead patients. We investigated the relationship between two sequential (6 h interval) measurements of plasma cTnI concentrations in brain-dead patients considered as potential heart donors. The first and the second TnIc values were correlated with an adjusted r2 value of 0.92 (p<0.001). Our results suggest therefore that it is not necessary to repeat the measurements, when the value of plasma cTnI concentration is taken into consideration in the algorithm for cardiac harvesting.

[Analysis of the criteria that contribute to the decision to harvest the heart in brain-dead organ donors]. / Analyse des critères qui participent à la décision de prélèvement cardiaque chez les patients en état de mort encéphalique.

OBJECTIVES: The number of cardiac transplantation procedures does not increase because of the lack of donor hearts despite an increase in the number of brain-dead organ donors. The criteria used to select a donor heart are not formally standardized. The aim of the present study was to analyze the criteria that contribute to the selection of a donor heart. TYPE OF STUDY: Descriptive, retrospective study. PATIENTS AND METHOD: Clinical parameters, the initial causes that lead to brain death, maximum doses of catecholamines, several biochemical markers of myocardial ischaemia/necrosis as well as several echocardiography criteria were extracted from a prospectively collected database. Univariate and multivariate (logistic regression) analyses were performed with the "harvested heart" as dependent variable and the above-cited independent variables. RESULTS: One hundred and eighty consecutive brain-dead patients admitted from 1st October 1998 to 31st December 2000 out of which 112 gave at least one organ were analyzed. Among these 112 patients, 59 (39 males and 20 females) were pre-selected as potential heart donors. Only 44 hearts were harvested. Logistic regression analysis showed that harvesting of the heart was more probable if the donor were a male, had no left ventricle systolic wall motion abnormalities, had low doses of norepinephrine and low serum troponin Ic concentrations. CONCLUSION: After an initial phase of selection, the final decision to harvest a heart is based on several criteria. These results should be an incentive to conceive a score that could allow a more formal decision process for heart harvesting.

Transplantation in Waldenstrom's macroglobulinemia--the French experience.

Published data on transplantation in Waldenstrom's macroglobulinemia (WM) are still limited. We present a retrospective multicentric study of 27 WM patients who underwent 19 autologous (median age, 54 years) and 10 allogeneic (median age, 46 years) transplantations. Median time between diagnosis and transplantation was 36 months; 66% of patients had received three or more treatment lines and 72 % had chemosensitive disease. High-dose therapy (HDT) and autologous transplantation induced a 95% response rate (RR), including 10 major responses. With a median follow-up of 18 months, 12 patients are alive at 10 to 81 months and eight are free of disease progression at 10 to 34 months. The toxic mortality rate (TRM) was 6%. Allogeneic transplantation was preceded by HDT in nine patients and by a nonmyeloablative regimen in one patient. The RR was 80%, including seven major responses. With a median follow-up of 20.5 months, six patients are alive and free of progression at 3 to 76 months. Four patients died, all from toxicity, resulting in a TRM of 40%. HDT followed by autologous transplantation is feasible in WM, even in heavily pretreated patients, with some prolonged responses but a high relapse rate. Conversely, allogeneic transplantation is more toxic, but likely induces a graft-versus-WM effect and may, for some patients, result in long-term disease control.

Facilitation of plateau potentials in turtle motoneurones by a pathway dependent on calcium and calmodulin.

1. The involvement of intracellular calcium and calmodulin in the modulation of plateau potentials in motoneurones was investigated using intracellular recordings from a spinal cord slice preparation. 2. Chelation of intracellular calcium with BAPTA-AM or inactivation of calmodulin with W-7 or trifluoperazine reduced the amplitude of depolarization-induced plateau potentials. Inactivation of calmodulin also inhibited facilitation of plateau potentials by activation of group I metabotropic glutamate receptors or muscarinic receptors. 3. In low-sodium medium and in the presence of tetraethylammonium and tetrodotoxin, calcium action potentials evoked by depolarization were followed by a short hyperpolarization ascribed to the calcium-activated non-selective cationic current (ICAN) and by a dihydropyridine-sensitive afterdepolarization. The amplitude of the afterdepolarization depended on the number of calcium spikes and was mediated by L-type calcium channels. 4. The dihydropyridine-sensitive afterdepolarization induced by calcium spikes was reduced by blockade of calmodulin. 5. It is proposed that plateau potentials in spinal motoneurones are facilitated by activation of a calcium-calmodulin-dependent pathway.

Dedifferentiation of intrinsic response properties of motoneurons in organotypic cultures of the spinal cord of the adult turtle.

Explant cultures from the spinal cord of adult turtles were established and used to study the sensitivity of the intrinsic response properties of motoneurons to the changes in connectivity and milieu imposed by isolation in culture. Transverse sections 700 microm thick were explanted on cover slips and maintained in roller-tube cultures in medium containing serum and the growth factors brain-derived neurotrophin factor (BDNF), neurotrophin-3 (NT3), glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). The gross morphology of acute sections was maintained after 4 weeks in culture. Cell bodies of motoneurons remained stainable in fixed cultures with an antibody against choline acetyltransferase (ChAT) throughout the culture period. During culture, motoneurons maintained stable resting membrane potentials and were contacted by functional synapses. The ability to generate action potentials was also preserved as was delayed inward rectification and generation of calcium spikes in the presence of tetra-ethyl ammonium (TEA). In response to depolarization, however, motoneurons presented strong outward rectification, and only 41% of the cells recorded from maintained the ability to fire repetitively. By the second week in culture, a fraction of motoneurons displayed fast and slow transient outward rectification and low-threshold calcium spikes, features not seen in turtle motoneurons in acute slices. On the other hand, properties mediated by L-type Ca2+ channels disappeared during the first few days in culture. Our observations show that the phenotypical intrinsic response properties of mature spinal motoneurons are modified in explant cultures. The properties acquired resemble the properties in juvenile motoneurons in several species of terrestrial vertebrates.

Cooperation of muscle and cutaneous afferents in the feedback of contraction to peroneal motoneurons.

Peroneal motoneurons were recorded intracellularly in anesthetized cats during sustained submaximal contractions of peroneus brevis muscle (PB) elicited by repetitive electrical stimulation of motor axons in the distal portion of cut ventral root filaments. Mechanical stimulation of the territory innervated by the superficial peroneal nerve (SP) was applied during contraction to assess the influence of afferents from this territory on the contraction-induced excitation of motoneurons. In 21 peroneal motoneurons in which PB contraction evoked excitatory potentials, a stimulation engaging mechanoreceptors located in the skin around toes was found to either enhance (in 12 motoneurons) or reduce (in 9 motoneurons) the contraction-induced excitatory potentials. Among positive effects, six showed simple summation of the responses to each individual stimulus, suggesting a convergence of afferent pathways on motoneurons. In six other motoneurons, complex interactions were observed, as may result from convergence at a premotoneuronal level. Among negative effects, a single instance was observed of inhibitory facilitation, as may result from convergence of cutaneous and muscular, possibly Ib, afferents on inhibitory interneurons. Several pathways, mediating either facilitory or inhibitory influences, are available for cooperation of muscle and cutaneous input, allowing flexibility of motoneuron activation in different tasks.

Effects on peroneal motoneurons of cutaneous afferents activated by mechanical or electrical stimulations.

The postsynaptic potentials elicited in peroneal motoneurons by either mechanical stimulation of cutaneous areas innervated by the superficial peroneal nerve (SP) or repetitive electrical stimulation of SP were compared in anesthetized cats. After denervation of the foot sparing only the territory of SP terminal branches, reproducible mechanical stimulations were applied by pressure on the plantar surface of the toes via a plastic disk attached to a servo-length device, causing a mild compression of toes. This stimulus evoked small but consistent postsynaptic potentials in every peroneal motoneuron. Weak stimuli elicited only excitatory postsynaptic potentials (EPSPs), whereas increase in stimulation strength allowed distinction of three patterns of response. In about one half of the sample, mechanical stimulation or trains of 20/s electric pulses at strengths up to six times the threshold of the most excitable fibers in the nerve evoked only EPSPs. Responses to electrical stimulation appeared with 3-7 ms central latencies, suggesting oligosynaptic pathways. In another, smaller fraction of the sample, inhibitory postsynaptic potentials (IPSPs) appeared with an increase of stimulation strength, and the last fraction showed a mixed pattern of excitation and inhibition. In 24 of 32 motoneurons where electrical and mechanical effects could be compared, the responses were similar, and in 6 others, they changed from pure excitation on mechanical stimulation to mixed on electrical stimulation. With both kinds of stimulation, stronger stimulations were required to evoke inhibitory postsynaptic potentials (IPSPs), which appeared at longer central latencies than EPSPs, indicating longer interneuronal pathways. The similarity of responses to mechanical and electrical stimulation in a majority of peroneal motoneurons suggests that the effects of commonly used electrical stimulation are good predictors of the responses of peroneal motoneurons to natural skin stimulation. The different types of responses to cutaneous afferents from SP territory reflect a complex connectivity allowing modulations of cutaneous reflex responses in various postures and gaits.

Development and regulation of response properties in spinal cord motoneurons.

The intrinsic response properties of spinal motoneurons determine how converging premotor neuronal input is translated into the final motor command transmitted to muscles. From the patchy data available it seems that these properties and their underlying currents are highly conserved in terrestrial vertebrates in terms of both phylogeny and ontogeny. Spinal motoneurons in adults are remarkably similar in many respects ranging from the resting membrane potential to pacemaker properties. Apart from the axolotls, spinal motoneurons from all species investigated have latent intrinsic response properties mediated by L-type Ca2+ channels. This mature phenotype is reached gradually during development through phases in which A-type potassium channels and T-type calcium channels are transiently expressed. The intrinsic response properties of mature spinal motoneurons are subject to short-term adjustments via metabotropic synaptic regulation of the properties of voltage-sensitive ion channels. Recent findings also suggest that regulation of channel expression may contribute to long-term changes in intrinsic response properties of motoneurons.

Evaluation of donor cardiac function for heart transplantation: experience of a French academic hospital.

OBJECTIVES: The diagnostic and therapeutic approaches for evaluation and management of cardiac function in brain-dead patients vary from country to country. The aim of the present study was to describe the results of the evaluation of brain-dead patients as potential cardiac donors in a French teaching hospital that manages the largest number of brain-dead patients in France. METHODS: Demographic parameters, the causes of brain death, clinical evolution, hemodynamic parameters, doses of inotropic and/or vasopressive drugs, the results of echocardiographic examination, and several biochemical markers of myocardial cell injury were retrospectively collected. RESULTS: Seventy-one consecutive brain-dead patients admitted to the intensive care unit of the Academic Hospital of Nancy from October 1st, 1998 to September 30, 1999 were analyzed. Twenty-nine patients were considered as potential heart donors: 22 males and 7 females aged 33 +/- 3 years (Mean + SEM). The cause of brain death was head trauma in 17 cases (59%), cerebrovascular disease in 10 cases (34%), and cerebral anoxia related to cardiac arrest in 2 cases (7%). Eighteen hearts (18/29 or 66%) were harvested and transplanted with a favorable outcome at one month in 17 cases. In 11 cases, the heart was not harvested, nine (9/29 or 31%) because of myocardial dysfunction upon subsequent echocardiographic examination and 2 because of the lack of matched recipients. CONCLUSION: Comparison of these results with those of other groups suggests that hormonal substitution with insulin and triiodothyronine in the presence of myocardial dysfunction could be of potential interest to correct myocardial dysfunction and increase the number of donor hearts.

Ca(2+)-activated nonselective cationic current (I(CAN)) in turtle motoneurons.

The presence of a calcium-activated nonspecific cationic (CAN) current in turtle motoneurons and its involvement in plateau potentials, bistability, and wind-up was investigated by intracellular recordings in a spinal cord slice preparation. In the presence of tetraethylammonium (TEA) and tetrodotoxin (TTX), calcium action potentials evoked by depolarizing current pulses were always followed by an afterdepolarization associated with a decrease in input resistance. The presence of the afterdepolarization depended on the calcium spike and not on membrane potential. Replacement of extracellular sodium by choline or N-methyl-D-glucamine (NMDG) reduced the afterdepolarization, confirming that it was mediated by a CAN current. Plateau potentials and wind-up were evoked in response to intracellular current pulses in the presence of agonist for different metabotropic receptors. Replacement of extracellular sodium by choline or NMDG did not abolish the generation of plateau potentials, bistability, or wind-up, showing that Na(+) was not the principal charge carrier. It is concluded that plateau potentials, bistability and wind-up in turtle motoneurons do not depend on a CAN current even though its presence can be detected.

Oscillatory interaction between dorsal root excitability and dorsal root potentials in the spinal cord of the turtle.

The response to dorsal root stimulation, at one to two times threshold, was investigated in the isolated cervical enlargement of the turtle spinal cord. At frequencies near 10 Hz the synaptic response in motoneurons and the cord dorsum potential, after an initial lag time, oscillated in amplitude with a period of more than 1 s. The mono- and polysynaptyic postsynaptic response in motoneurons, the pre- and postsynaptic component of the cord dorsum potential and the dorsal root potential oscillated in synchrony. These oscillations were only observed with stimulus frequencies in the range 9-11 Hz. The oscillating response could only be evoked from stimulus sites to which dorsal root potentials were conducted from the spinal cord (2-3 mm). At more distant stimulus sites cyclic variations in amplitude of the cord dorsum potential and the synaptic response in motoneurons were not observed. During an oscillating spinal response to a stimulus train in one dorsal root filament, the response evoked by a stimulus in another short filament (2-3 mm) from the same root varied in amplitude with the induced oscillation. The spinal response to a stimulus in a longer filament (i.e. more than 3 mm) did not oscillate. It is argued that the oscillating responses described rely on interactions between distributed elements rather than on unit oscillators. We also show that primary afferent transmission is unaffected by the substantial variations in dorsal root potentials during oscillations.

Local facilitation of plateau potentials in dendrites of turtle motoneurones by synaptic activation of metabotropic receptors.

1. The spatial distribution of synaptic facilitation of plateau potentials in dendrites of motoneurones was investigated in transverse sections of the spinal cord of the turtle using differential polarization by applied electric fields. 2. The excitability of motoneurones in response to depolarizing current pulses was increased following brief activation of either the dorsolateral funiculus (DLF) or the medial funiculus (MF) even when synaptic potentials were eliminated by antagonists of ionotropic receptors. 3. The medial and lateral compartments of motoneurones were differentially polarized by the electric field generated by passing current between two electrodes on either side of the preparation. In one direction of the field lateral dendrites were depolarized while the cell body and medial dendrites were hyperpolarized (S- configuration). With current in the opposite direction the cell body and medial dendrites were depolarized while lateral dendrites were hyperpolarized (S + configuration). 4. Following brief activation of the DLF the excitability and the generation of plateau potentials were facilitated during differential depolarization of the lateral dendrites but not during differential depolarization of the cell body and medial dendrites. Following brief activation of the MF the excitability and generation of plateau potentials were facilitated during differential depolarization of the cell body and medial dendrites but not during differential depolarization of the lateral dendrites. 5. It is concluded that the synaptic facilitation of the dihydropyridine-sensitive response to depolarization is compartmentalized in turtle motoneurones.

Metabotropic synaptic regulation of intrinsic response properties of turtle spinal motoneurones.

1. The effect of a brief train of electric stimuli in the dorsolateral funiculus on the intrinsic response properties of turtle motoneurones was investigated in transverse sections of the spinal cord in vitro. 2. Even when glutamatergic, GABAergic and glycinergic ionotropic synaptic transmission was blocked by antagonists of AMPA, NMDA, glycine and GABA receptors, dorsolateral funiculus (DLF) stimulation induced a facilitation of plateau potentials during current clamp and the underlying inward current in voltage clamp. This facilitation lasted more than 10 s. 3. The plateau potential and the facilitation by DLF stimulation was absent in the presence of 10 microM nifedipine. The DLF-induced facilitation was reduced by antagonists of 5-HT1A, group 1 metabotropic glutamate receptors and muscarine receptors. 4. These findings suggest that the intrinsic properties of spinal motoneurones are dynamically regulated by afferent synaptic activity. These afferents can be of spinal and extraspinal origin. Continuous regulation of intrinsic response properties could be a mechanism for motor flexibility.

Short-latency synaptic patterns among cat peroneal motoneurons.

Motoneurons innervating peroneal muscles in the cat leg (PB, PT and PL, respectively, for peroneus brevis, tertius and longus) were examined for their connections with afferents from these and other leg muscles and with cutaneous afferents. The aim was to investigate (1) whether inputs from nearby muscles and cutaneous areas are likely to assist or oppose the excitation elicited in peroneal motoneurons by PB contractions, and (2) whether reflex connectivity might allow distinction of alpha (i.e. motoneurons innervating skeletal muscle fibres) and beta (i.e. motoneurons innervating both skeletal and intrafusal muscle fibres) subgroups among PB and PT motoneurons. In the three peroneal pools, every motoneuron had excitatory monosynaptic connections with Ia afferents from each of the three peroneal muscles, and nearly every motoneuron received di- or trisynaptic excitation from low-threshold cutaneous afferents in sural or superficial peroneal nerves. Inputs from these sources might facilitate the contraction-induced positive feedback. In contrast, the patterns of short-latency synaptic connections with group I afferents from pretibial flexor and post-tibial extensor muscles were heterogeneous among peroneal motoneurons but did not point to any specific beta pattern.

Heterogeneity of contraction-induced effects in neurons of the cat dorsal spinocerebellar tract.

1. Clarke's column neurons of the dorsal spinocerebellar tract (DSCT) were recorded intracellularly in anaesthetized cats during weak sustained contractions of triceps surae (TS) produced by direct electrical stimulation of the muscle. 2. Of 145 DSCT neurons, 77 (53%) were contraction sensitive suggesting that information about weak contraction of a limited number of muscles is widely distributed among DSCT neurons. Four types of effects were observed in individual neurons during TS contractions. 3. In the first group of 11 DSCT neurons (14% of the contraction-sensitive cells), the effect was excitation persisting throughout the duration of contractions. These responses were ascribed to actions of afferents from contraction-activated tendon organs. 4. In a second group of 15 neurons (20% of the contraction-sensitive cells), quickly declining excitatory potentials were recorded during sustained TS contractions. By analogy with previous observations of contraction-induced effects in motoneurons, the decline of excitation might be explained by contraction-induced presynaptic inhibition of group I afferents in Clarke's column. 5. Declining inhibitions, resembling those previously observed in homonymous and synergic motoneurons, were recorded in 49% of contraction-sensitive DSCT neurons. This appears in keeping with the fact that interneurons mediating Ib inhibition to motoneurons project axon collaterals to DSCT neurons. Presynaptic inhibition of Ib fibres might therefore cause parallel reductions of inhibitory potentials in motoneurons and in DSCT neurons. 6. In a final group of 13 neurons, mixed excitatory and inhibitory effects were observed during TS contractions. Such DSCT neurons might monitor the excitability of Ib interneurons by integration of information about input to and output from these neurons. 7. The non-uniform patterns of DSCT responses to TS contractions suggest complex processing of information on ankle extensor activity in cerebellum. Phasic signalling of contraction onset is observed in many DSCT neurons while others carry messages about duration and strength of contraction.