The role of the dorsolateral prefrontal cortex during sequence learning is specific for spatial information.

Many studies have implicated the dorsolateral prefrontal cortex in the acquisition of skill, including procedural sequence learning. However, the specific role it performs in sequence learning has remained uncertain. This type of skill has been intensively studied using the serial reaction time task. We used three versions of this task: a standard task where the position of the stimulus cued the response; a non-standard task where the color of the stimulus was related to the correct response; and a combined task where both the color and position simultaneously cued the response. We refer to each of these tasks based upon the cues available for guiding learning as position, color and combined tasks. The combined task usually shows an enhancement of skill acquisition, a result of being driven by two simultaneous and congruent cues. Prior to the performance of each of these tasks the function of the dorsolateral prefrontal cortex was disrupted using repetitive transcranial magnetic stimulation. This completely prevented learning within the position task, while sequence learning occurred to a similar extent in both the color and combined tasks. So, following prefrontal stimulation the expected learning enhancement in the combined task was lost, consistent with only a color cue being available to guide sequence learning in the combined task. Neither of these effects was observed following stimulation at the parietal cortex. Hence the critical role played by the dorsolateral prefrontal cortex in sequence learning is related exclusively to spatial cues. We suggest that the dorsolateral prefrontal cortex operates over the short term to retain and manipulate spatial information to allow cortical and subcortical structures to learn a predictable sequence of actions. Such functions may emerge from the broader role the dorsolateral prefrontal cortex has in spatial working memory. These results argue against the dorsolateral prefrontal cortex constituting part of the neuronal substrate responsible for general aspects of implicit or explicit sequence learning.     

Medial temporal lobe involvement in an implicit memory task: evidence of collaborating implicit and explicit memory systems from FMRI and Alzheimer's disease

We used a prototype extraction task to assess implicit learning of a meaningful novel visual category. Cortical activation was monitored in young adults with functional magnetic resonance imaging. We observed occipital deactivation at test consistent with perceptually based implicit learning, and lateral temporal cortex deactivation reflecting implicit acquisition of the category's semantic nature. Medial temporal lobe (MTL) activation during exposure and test suggested involvement of explicit memory as well. Behavioral performance of Alzheimer's disease (AD) patients and healthy seniors was also assessed, and AD performance was correlated with gray matter volume using voxel-based morphometry. AD patients showed learning, consistent with preserved implicit memory, and confirming that AD patients' implicit memory is not limited to abstract patterns. However, patients were somewhat impaired relative to healthy seniors. Occipital and lateral temporal cortical volume correlated with successful AD patient performance, and thus overlapped with young adults' areas of deactivation. Patients' severe MTL atrophy precluded involvement of this region. AD patients thus appear to engage a cortically based implicit memory mechanism, whereas their relative deficit on this task may reflect their MTL disease. These findings suggest that implicit and explicit memory systems collaborate in neurologically intact individuals performing an ostensibly implicit memory task.     

Familiarity and conceptual priming engage distinct cortical networks

Familiarity refers to an explicit recognition experience without any necessary retrieval of specific detail related to the episode during which initial learning transpired. Prior experience can also implicitly influence subsequent processing through a memory phenomenon termed conceptual priming, which occurs without explicit awareness of recognition. Resolving current theoretical controversy on relationships between familiarity and conceptual priming requires a clarification of their neural substrates. Accordingly, we obtained functional magnetic resonance images in a novel paradigm for separately assessing neural correlates of familiarity and conceptual priming using famous and nonfamous faces. Conceptual priming, as shown by more accurate behavioral responses to strongly conceptually primed than to weakly conceptually primed faces, was associated with activity reductions in left prefrontal cortex, whereas familiarity was associated with activity enhancements in right parietal cortex for more-familiar compared with less-familiar faces. This neuroimaging evidence implicates separate neurocognitive processes operative in explicit stimulus recognition versus implicit conceptual priming.     

Regional brain activation during concurrent implicit and explicit sequence learning

We used event-related fMRI to identify the brain regions engaged during explicit and implicit sequence learning (ESL and ISL, respectively). Twenty-four subjects performed a concurrent ESL and ISL task. Behavior showed learning in both conditions. Prefrontal (PFC), striatal, anterior cingulate cortex (ACC) and visual regions (V1, V2 and V3) were engaged during both ESL and ISL. With ESL there was increased activity in the visual regions on the predictable (i.e. learned pattern) trials. With ISL, however, there was a relative decrease in activity in visual regions. The opposite patterns in the visual regions highlight the different effects of ESL and ISL. The learning process was distinguished from the result of learning, by fitting subjects' functional magnetic resonance imaging data to their learning curve. This analysis revealed more extensive PFC activity during ESL and caudal ACC activity specific for the result of learning analysis, when the expected response was violated. Our results suggest a relative dissociation of the brain regions engaged during ESL and ISL, whereby ESL and ISL can be viewed as partially distinct but overlapping parallel processes.     

Altered bidirectional plasticity and reduced implicit motor learning in concussed athletes

Persistent motor/cognitive alterations and increased prevalence of Alzheimer's disease are known consequences of recurrent sports concussions, the most prevalent cause of mild traumatic brain injury (TBI) among youth. Animal models of TBI demonstrated that impaired learning was related to persistent synaptic plasticity suppression in the form of long-term potentiation (LTP) and depression (LTD). In humans, single and repeated concussive injuries lead to lifelong and cumulative enhancements of gamma-aminobutyric acid (GABA)-mediated inhibition, which is known to suppress LTP/LTD plasticity. To test the hypothesis that increased GABAergic inhibition after repeated concussions suppresses LTP/LTD and contributes to learning impairments, we used a paired associative stimulation (PAS) protocol to induce LTP/LTD-like effects in primary motor cortex (M1) jointly with an implicit motor learning task (serial reaction time task, SRTT). Our results indicate that repeated concussions induced persistent elevations of GABA(B)-mediated intracortical inhibition in M1, which was associated with suppressed PAS-induced LTP/LTD-like synaptic plasticity. This synaptic plasticity suppression was related to reduced implicit motor learning on the SRTT task relative to normal LTP/LTD-like synaptic plasticity in unconcussed teammates. These findings identify GABA neurotransmission alterations after repeated concussions and suggest that impaired learning after multiple concussions could at least partly be related to compromised GABA-dependent LTP/LTD synaptic plasticity.     

An Investigation of Learning during Propofol Sedation and Anesthesia Using the Process Dissociation Procedure

Background: Many studies have shown that patients may remember words learned during apparently adequate anesthesia. Performance on memory tests may be influenced by explicit and implicit memory. We used the process dissociation procedure to estimate implicit and explicit memory for words presented during sedation or anesthesia.

Methods: We investigated intraoperative learning in 72 women undergoing pervaginal oocyte collection during propofol and alfentanil infusion. One word list was played once before infusion, another was played 10 times during surgery. Venous blood was taken for propofol assay at the end of the intraoperative list. Behavioral measures of anesthetic depth (eyelash reflex, hand squeeze response to command) were recorded and used to adjust the dose of anesthetic where clinically appropriate. On recovery, memory was assessed using an auditory word stem completion test with inclusion and exclusion instructions.

Results: The mean blood propofol concentration was 2.5 [mu]g/ml (median, 2.3 [mu]g/ml; range, 0.7-6.1 [mu]g/ml). Mean alfentanil dose was 2.1 mg (median, 2.0 mg; range, 1.2-3.4 mg). Comparison of target and distractor hits in the inclusion condition showed memory for preoperative words only. However, the process dissociation procedure estimates showed explicit (mean, 0.18;P < 0.001) and implicit (mean, 0.05;P < 0.05) memory for the preoperative words, and a small amount of explicit memory for the intraoperative words (mean, 0.06; 95% confidence interval, 0.01-0.10). Memory performance did not differ between the 17 patients who consistently responded to command and eyelash reflex and the 32 patients who remained unresponsive. Blood propofol concentration and alfentanil dose did not correlate with memory for the intraoperative list.     

Face repetition effects in implicit and explicit memory tests as measured by fMRI.

Recent parallels between neurophysiological and neuroimaging findings suggest that repeated stimulus processing produces decreased responses in brain regions associated with that processing--a 'repetition suppression' effect. In the present study, volunteers performed two tasks on repeated presentation of famous and unfamiliar faces during functional magnetic resonance imaging (fMRI). In the implicit task, they made fame-judgements (regardless of repetition); in the explicit task, they made episodic recognition judgements (regardless of familiarity). Only in the implicit task was repetition suppression observed: for famous faces in a right lateral fusiform region, and for both famous and unfamiliar faces in a left inferior occipital region. Repetition suppression is therefore not an automatic consequence of repeated perceptual processing of stimuli.     

Implications of basic science research for brain injury rehabilitation: a focus on intact learning mechanisms

Within a theoretical framework for rehabilitation that distinguishes between automatic and controlled processes, this article reviews basic science research and addresses the following issues: What cognitive abilities remain relatively intact after severe traumatic brain injury, and how can we incorporate intact skills into rehabilitative techniques? The reviewed research indicates that individuals with severe traumatic brain injury (a) generally perform similar to controls on cognitive tasks (or task components) that require automatic and implicit processes as opposed to consciously controlled processes; (b) can learn through implicit learning mechanisms; and (c) can acquire and use automatic processes in complex, cognitive task performance.     

An investigation of learning during propofol sedation and anesthesia using the process dissociation procedure

BACKGROUND: Many studies have shown that patients may remember words learned during apparently adequate anesthesia. Performance on memory tests may be influenced by explicit and implicit memory. We used the process dissociation procedure to estimate implicit and explicit memory for words presented during sedation or anesthesia. METHODS: We investigated intraoperative learning in 72 women undergoing pervaginal oocyte collection during propofol and alfentanil infusion. One word list was played once before infusion, another was played 10 times during surgery. Venous blood was taken for propofol assay at the end of the intraoperative list. Behavioral measures of anesthetic depth (eyelash reflex, hand squeeze response to command) were recorded and used to adjust the dose of anesthetic where clinically appropriate. On recovery, memory was assessed using an auditory word stem completion test with inclusion and exclusion instructions. RESULTS: The mean blood propofol concentration was 2.5 microg/ml (median, 2.3 microg/ml; range, 0.7-6.1 microg/ml). Mean alfentanil dose was 2.1 mg (median, 2.0 mg; range, 1.2-3.4 mg). Comparison of target and distractor hits in the inclusion condition showed memory for preoperative words only. However, the process dissociation procedure estimates showed explicit (mean, 0.18; P < 0.001) and implicit (mean, 0.05; P < 0.05) memory for the preoperative words, and a small amount of explicit memory for the intraoperative words (mean, 0.06; 95% confidence interval, 0.01-0.10). Memory performance did not differ between the 17 patients who consistently responded to command and eyelash reflex and the 32 patients who remained unresponsive. Blood propofol concentration and alfentanil dose did not correlate with memory for the intraoperative list. CONCLUSIONS: There was no unprompted recall of surgery, but the process dissociation procedure showed memory for words presented during surgery. This memory was apparently explicit but did not correlate with the measures of depth of anesthesia used.     

Wachzustände während Allgemeinanästhesie Definition,Häufigkeit,klinische Relevanz,Ursachen, Vermeidung und medikolegale Aspekte

The possibility that a patient during general anaesthesia is aware of the operation going on and aware of severe pain that might be remembered postoperatively must be very alarming to patients and anaesthetists alike. Furthermore, there is experimental evidence showing that conscious recall of intraoperative events is only the tip of an iceberg; it seems very probable that there is even a higher incidence of unconscious perception during general anaesthesia. Therefore, the following stages of intraoperative awareness must be distinguished: (1) conscious awareness with explicit recall and with severe pain; (2) conscious awareness with explicit recall but no complaints of pain; (3) conscious awareness without explicit recall and possible implicit recall; (4) subconscious awareness without explicit recall and possible implicit recall; (5) no awareness. The incidence of conscious awareness with explicit recall and severe pain has been estimated at less frequent than 1/3000 general anaesthetics. Conscious awareness with explicit recall but no complaints of pain has been reported in the literature with an incidence of 0.5–2%. With 7–72%, conscious awareness without explicit recall and possible implicit recall shows a very wide range of variation and its occurrence probably depends on the anaesthetic drugs used. Subconscious awareness with possible implicit recall has an incidence of up to 80%, but there are many methodological problems in demonstrating implicit memory of intraoperative events. Reports of intraoperative awareness do not come exclusively from cardiac surgery and obstetrics, but also from all other operative specialities. Postoperatively, patients who experienced intraoperative awareness may develop a so-called post-traumatic stress syndrome. Symptoms involve re-experiencing the event awake or in dreams, sleep disturbances, depression, avoidance of stimuli associated with the event. The probability of the development of the post-traumatic stress syndrome seems to coincide with the experience of severe pain. When a patient complains of intraoperative awareness postoperatively the anaesthesiologist should discuss the event frankly with the patient. When the symptoms of the post-traumatic stress syndrome persist a psychotherapy should follow. Causes for intraoperative awareness may be: equipment failure, too-light anaesthesia, e.g. for a caesarean section or for emergency surgery in severely injured or polytraumatized patients, during cardiac surgery, bronchoscopy or difficult intubation. There is interindividual variability in anaesthetic effect; for example, chronic drug or alcohol abuse or overweight may make increased anaesthetic doses necessary. They are at risk for intraoperative awareness. Some general anaesthetics or anaesthetic procedures, e.g. the combination of a relaxant and N₂O, opioid mono-anaesthetics, or opioids combined with benzodiazepines, seem to involve a higher risk of intraoperative awareness than do volatile anaesthetics. The bases of litigation are medical malpractice, breach of contract by the anaesthesiologist or lack of informed consent from the patient. Therefore, patients who are at risk of intraoperative awareness should be given detailed information on this special risk before the operation.     

Two distinct neural mechanisms for category-selective responses

The cognitive and neural mechanisms mediating category-selective responses in the human brain remain controversial. Using functional magnetic resonance imaging and effective connectivity analyses (Dynamic Causal Modelling), we investigated animal- and tool-selective responses by manipulating stimulus modality (pictures versus words) and task (implicit versus explicit semantic). We dissociated two distinct mechanisms that engender category selectivity: in the ventral occipito-temporal cortex, tool-selective responses were observed irrespective of task, greater for pictures and mediated by bottom-up effects. In a left temporo-parietal action system, tool-selective responses were observed irrespective of modality, greater for explicit semantic tasks and mediated by top-down modulation from the left prefrontal cortex. These distinct activation and connectivity patterns suggest that the two systems support different cognitive operations, with the ventral occipito-temporal regions engaged in structural processing and the dorsal visuo-motor system in strategic semantic processing. Consistent with current semantic theories, explicit semantic processing of tools might thus rely on reactivating their associated action representations via top-down modulation. In terms of neuronal mechanisms, the category selectivity may be mediated by distinct top-down (task-dependent) and bottom-up (stimulus-dependent) mechanisms.     

Absence of memory for intra-operative information during surgery with total intravenous anaesthesia

While using the isolated forearm technique, we wished to determinewhether patients who did not respond to commands during generalanaesthesia with a total intravenous technique (propofol andalfentanil with atracurium) had any evidence of post-operativeexplicit or implicit memory. Forty women undergoing major gynaecologicalsurgery were randomized, in a double-blind design, to hear twodifferent tapes during surgery. Psychological tests of explicitand implicit memory were conducted within 2 h of surgery. Therewas no evidence of implicit or explicit memory, nor any recall,in the seven women who responded to commands during surgery.We conclude that during total intravenous anaesthesia with propofoland alfentanil, there is no evidence that learning takes placewhen anaesthesia is adequate. Furthermore, with this anaesthetictechnique, it would seem that—provided any period of patientresponsiveness is short and that unconsciousness is inducedrapidly again—there is no evidence of implicit or explicitmemory. Br J Anaesth 2001; 86: 196–202     

Examining Electrostatic Influences on Base-Flipping: A Comparison of TIP3P and GB Solvent Models

Recently, it was demonstrated that implicit solvent models were capable of generating stable B-form DNA structures. Specifically, generalized Born (GB) implicit solvent models have improved regarding the solvation of conformational sampling of DNA [1, 2]. Here, we examine the performance of the GBSW and GBMV models in CHARMM for characterizing base flipping free energy profiles of undamaged and damaged DNA bases. Umbrella sampling of the base flipping process was performed for the bases cytosine, uracil and xanthine. The umbrella sampling simulations were carried-out with both explicit (TIP3P) and implicit (GB) solvent in order to establish the impact of the solvent model on base flipping. Overall, base flipping potential of mean force (PMF) profiles generated with GB solvent resulted in a greater free energy difference of flipping than profiles generated with TIP3P. One of the significant differences between implicit and explicit solvent models is the approximation of solute-solvent interactions in implicit solvent models. We calculated electrostatic interaction energies between explicit water molecules and the base targeted for flipping. These interaction energies were calculated over the base flipping reaction coordinate to illustrate the stabilizing effect of the explicit water molecules on the flipped-out state. It is known that nucleic base pair hydrogen bonds also influenced the free energy of flipping since these favorable interactions must be broken in order for a base to flip-out of the helix. The Watson-Crick base pair hydrogen bond fractions were calculated over the umbrella sampling simulation windows in order to determine the effect of base pair interactions on the base flipping free energy. It is shown that interaction energies between the flipping base and explicit water molecules are responsible for the lower base flipping free energy difference in the explicit solvent PMF profiles.     

The effect of analgesic state on implicit learning during propofol anesthesia in volunteers

Noxious stimulation may enhance implicit learning during general anesthesia. It is unknown, however, whether analgesic state can influence this memory processing. Twenty healthy adult volunteers were enrolled our prospective, double-blinded, controlled experiments. Anesthesia was induced with a propofol target controlled infusion (TCI), titrated in step-wise increments to loss of consciousness. In phase A, a 10-word list was played to the subjects while a noxious stimulus was applied (hand immersion in cold water at 2-4 degrees C). In phase B, a remifentanil TCI infusion was added to the steady-state propofol TCI anesthesia, and titrated to loss of hand movement on cold water immersion. A second 10-word list was then played while maintaining the hand in cold water. Memory testing, 2 hours post-recovery revealed no evidence of explicit memory in any subject during either phase of the study. During phase A, the word stem completion test revealed implicit learning for played words. In contrast, no implicit memory was detected during phase B. This study indicates that analgesia with remifentanil TCI (titrated to loss of movement on noxious stimulation), prevented implicit memory processing during stable propofol anesthesia in healthy adult volunteers.     

Time Implicit Unified Gas Kinetic Scheme for 3D Multi-Group Neutron Transport Simulation

In this paper, a time implicit unified gas kinetic scheme (IUGKS) for 3D multi-group neutron transport equation with delayed neutron is developed. The explicit scheme, implicit 1st-order backward Euler scheme, and 2nd-order Crank-Nicholson scheme, become the subsets of the current IUGKS. In neutron transport, the microscopic angular flux and the macroscopic scalar flux are fully coupled in an implicit way with the combination of dual-time step technique for the convergence acceleration of unsteady evolution. In IUGKS, the computational time step is no longer limited by the Courant-Friedrichs-Lewy (CFL) condition, which improves the computational efficiency in both steady and unsteady simulations with a large time step. Mathematically, the current scheme has the asymptotic preserving (AP) property in recovering automatically the diffusion solution in the continuum regime. Since the explicit scanning along neutron traveling direction within the computational domain is not needed in IUGKS, the scheme can be easily extended to multi-dimensional and parallel computations. The numerical tests demonstrate that the IUGKS has high computational efficiency, high accuracy, and strong robustness when compared with other schemes, such as the explicit UGKS, the commonly used finite difference, and finite volume methods. This study shows that the IUGKS can be used faithfully to study neutron transport in practical engineering applications.     

Dependence of explicit and implicit memory on hypnotic state in trauma patients

BACKGROUND: It is still unclear whether memory of intraoperative events results entirely from moments of inadequate anesthesia. The current study was designed to determine whether the probability of memory declines with increasing depth of the hypnotic state. METHOD: A list of words was played via headphones during surgery to patients who had suffered acute trauma. Several commonly used indicators of anesthetic effect, including the bispectral index, were recorded during word presentation. First, these indicators served as predictors of the memory performance in a postoperative word stem completion test. Second, general memory performance observed in the first part was separated into explicit and implicit memory using the process dissociation procedure, and then two models of memory were compared: One model assumed that the probability of explicit and implicit memory decreases with increasing depth of hypnotic state (individual differences model), whereas the other assumed equal memory performance for all patients regardless of their level of hypnotic state. RESULTS: General memory performance declined with decreasing bispectral index values. None of the other indicators of hypnotic state were related to general memory performance. Memory was still significant at bispectral index levels between 60 and 40. A comparison of the two models of memory resulted in a better fit of the individual differences model, thus providing evidence of a dependence of explicit and implicit memory on the hypnotic state. Quantification of explicit and implicit memory revealed a significant implicit but no reliable explicit memory performance. CONCLUSIONS: This study clearly indicates that memory is related to the depth of hypnosis. The observed memory performance should be interpreted in terms of implicit memory. Auditory information processing occurred at bispectral index levels between 60 and 40.     

Early cortical distinction between memories that pertain to ongoing reality and memories that don't.

Patients with anterior limbic lesions, in particular of the posterior orbitofrontal cortex, often act on the basis of memories that do not relate to ongoing reality and justify their behavior with invented stories that can mostly be traced back to real events (spontaneous confabulation). Recent studies demonstrated that the patients fail to suppress activated memory traces that do not pertain to ongoing reality. In the present study, we used a similar paradigm and high-resolution event-related potentials to explore when this suppression happens. Healthy subjects made two runs of a continuous recognition task, composed of the same set of pictures, and were requested to indicate picture recurrences only within the ongoing run. Thus, performance in the first run depends on new learning, whereas the second run requires the ability to realize whether a picture is solely familiar from its occurrence in the previous run ('distracter') or whether it has already appeared in the ongoing second run ('target'). We find that correct rejection (suppression) of currently irrelevant pictures (distracters of run 2) is associated with absent negative deflection of a frontal potential and absence of a specific cortical potential map configuration after 220-300 ms. By contrast, learning and recognition of repeatedly presented information is associated with cortical amplitude modulation after 400-480 ms. These findings indicate that by the time the content of a mental association is recognized and consolidated, its cortical representation has already been adjusted according to whether it relates to ongoing reality or not. This sequence may also explain the ability to distinguish between the memory of a true event and the memory of a thought.     

Effect of midazolam on memory: a study of process dissociation procedure and functional magnetic resonance imaging

To assess the effects of midazolam on explicit and implicit memories, 12 volunteers were randomly divided into the two groups: one with an Observer’s Assessment of Alertness/Sedation score of 3 (mild sedation) and one with a score of 1 (deep sedation). Blood oxygen‐level‐dependent functional magnetic resonance imaging was measured before and during an auditory stimulus, then with midazolam sedation, and then during a second auditory stimulus with continuous midazolam sedation. After 4 h, explicit and implicit memories were assessed. There was no evidence of explicit memory at the two levels of midazolam sedation. Implicit memory was retained at a mild level of midazolam sedation but absent at a deep level of midazolam sedation. At a mild level of midazolam sedation, activation of all brain areas by auditory stimulus (as measured by functional magnetic resonance imaging) was uninhibited. However, a deep level of midazolam sedation depressed activation of the superior temporal gyrus by auditory stimulus. We conclude that midazolam does not abolish implicit memory at a mild sedation level, but can abolish both explicit and implicit memories at a deep sedation level. The superior temporal gyrus may be one of the target areas.     

BDNF Polymorphism-Dependent OFC and DLPFC Plasticity Differentially Moderates Implicit and Explicit Bias

This study examined the role of orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) plasticity in controlling implicit and explicit social biases. Normal controls and patients with varied OFC and DLPFC lesion size and single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene, which promotes (methionine-valine [Met/Val] SNP) or stifles (valine-valine [Val/Val] SNP) plasticity in damaged PFC regions, completed measures of implicit and explicit social bias. Patients and controls demonstrated comparable levels of implicit bias, but patients with Met/Val SNPs exhibited less implicit bias when they had smaller OFC lesions compared with Val/Val patients with similar size lesions and those with large OFC lesions. Both patients and controls demonstrated patterns of explicit bias consistent with hypotheses. Patients with Met/Val SNPs exhibited less explicit bias when they had smaller DLPFC lesions sizes compared with Val/Val patients with similar size lesions and those with large DLPFC lesions. OFC lesion size and BDNF SNP type did not moderate explicit bias; DLPFC lesion size and BDNF SNP type did not moderate implicit bias (nor did other medial or lateral regions). Findings suggest that plasticity within specific PFC regions modulates the type and degree of social bias that individuals' exhibit.     

Suppression of mixed leukocyte culture using leukocytes from normal individuals, uremic patients, and allograft recipients

The suppressor cell function of peripheral blood mononuclear leukocytes (MNLs) from normal individuals, renal failure patients, and allograft recipients was evaluated using a suppressor cell assay wherein putative suppressors were added at the initiation of a third-party, one-way mixed leukocyte culture (MLC). MNLs from renal allograft recipients displayed the greatest suppressive activity (P less than 0.05): 50% suppression was achieved with 0.5 x 10(5) MNLs from allograft recipients, 2 x 10(5) MNLs from end stage renal disease patients, or 4 x 10(5) MNLs from normal individuals. The frequency of tests displaying positive MLC suppression using 1 x 10(5) MNLs was 90% (383 of 426) for allograft recipients compared with 60% (83 of 138) for renal failure patients and 28.2% (29 of 103) for normal individuals (P less than 0.01). The suppression displayed by 1 x 10(5) MNLs from potential allograft recipients receiving more than five pretransplant blood transfusions (BTs) was equal to that of 4 x 10(5) MNLS from patients receiving less than five BTs (P less than 0.05). Moreover, the frequency of positive MLC suppression from patients treated with more than five versus less than five BTs was 80% versus 40% (P less than 0.001). Although suppression of MLC appeared to be mainly dependent on an esterase (+)-adherent cell, there was no significant difference between the percentage of esterase (+) cells in unfractionated MNLs from the three groups of individuals, suggesting that MLC suppression was attributable to the functional performance rather than the number of suppressor MNLs. Preliminary data suggest a relationship between the level of MLC suppressive activity detected pretransplant and the outcome of the allograft at 6 months.