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PubMed1991

8th Duncan Memorial Lecture. Childhood cancer and nuclear installations.

So where are we now? I think the first thing to say is that there is a well-established excess around Sellafield of childhood leukaemia, although excesses around other nuclear sites are of a lower magnitude. The excess near Sellafield is strongly associated with fathers having high exposure to external whole-body penetrating radiation while working at the installation before their child's conception. But is this association pointing towards a causal mechanism? One possibility is genetic damage, but most geneticists and radiobiologists would consider that the levels of occupational exposure, even at Sellafield, are too low for this to be a plausible pathway on current knowledge. This is based to some extent on the lack of any similar effect among children born subsequently to Japanese survivors of the atomic bombs--however, the scenario is somewhat different contrasting a high short-term exposure with a lower long-term exposure. As well, some workers at Sellafield will also be exposed to radionuclides, such as plutonium, which we have not yet been able to analyse for. In addition, there are other exposures in a complex environment which may or may not be relevant. One experimental study in the laboratory using animals supports the idea that a pathway through irradiation of the parents is plausible, although this one result needs replication. Other causes have been suggested for the excess childhood leukaemia levels in particular around nuclear establishments--these include population movement, implicating viruses that have long been considered to be associated with childhood leukaemia, high rates in isolated communities, and also selection of areas for nuclear sites that have a natural propensity to high rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1975

Neuronal correlates of an encephalopathy associated with aluminum neurofibrillary degeneration.

A previous study reported that the intracranial injection of a soluble aluminum salt induced an encephalopathy which may serve as a useful animal model of dementia. An early sign of the encephalopathy in cats was a progressive decrement in both the performance of a short-term visual retention task and acquisition of a conditioned avoidance response in the presence of normal visual discrimination. This study reports that 10 days following the application of aluminum (AlCl3) there was an absence in cat visual cortex of neurons with spontaneous frequencies between 7 and 12 spikes/sec. The loss was associated with neurofibrillary degeneration and aluminum concentrations in lateral gyrus between 4 and 6 mug/g dry weight. The remaining neurons decreased their variability of response to identical visual stimuli and increased their probability of response and frequency of discharge.

Aluminum↗

PubMed1992

Development and function of dendritic cells in health and disease.

The life history of dendritic cells (DC) is now established from their origins from bone marrow stem cells, their distribution through blood to the tissues, and their movement via afferent lymph to lymph nodes for the initiation of immune responses. Bone-marrow stem cells, and occasional stem cells in peripheral blood (about 1 per 10(5) mononuclear cells), can give rise both to DC and macrophages (MO). In addition to stem cells in blood, after short-term culture of mononuclear cells, three major morphologic types of DC can be separated (types I-III), which probably represent the maturational pathway of this cell type; type II cells resemble tissue DC such as Langerhans cells and type III have a veiled morphology similar to that seen in cells of afferent lymph and in the interdigitating cells of the paracortex of lymph nodes. Functionally, DC cultured from peripheral blood are able to acquire large antigens and process them like Langerhans cells of the skin. They can also present antigens to stimulate primary T-cell responses, a property associated with lymph node DC. In tissues, DC appear to act as outposts of the immune system, acquire antigens, and, particularly in primary responses, carry the antigens to lymph nodes where they initiate T-cell responses. In secondary responses, activation of memory T cells in the periphery and the acquisition of antigen/antibody complexes by follicular dendritic cells of the lymph node follicles, which stimulate B cell memory, may be more important pathways for immune activation. DC may play a role in the development of many immunologic diseases including cancer, autoimmunity, and acquired immunodeficiency syndrome (AIDS).

Acquired Immunodeficiency Syndrome↗

PubMed1978

Short-term serial tactual recall: effects of grouping on tactually probed recall of Braille letters and nonsense shapes by blind children.

The study tested the hypothesis that grouping has adverse effects on the recall of tactual shapes but facilitates the recall of tactual letters on the assumption that this depends on different processes. A further question was the relation of grouping to letter recall span (set-size). Tactually probed recall of tactually presented serial nonsense and letter shapes by blind children was tested under grouped and ungrouped conditions. Results showed a highly significant interaction between list type and grouping, and a (smaller) higher order interaction between set size list type and grouping, in the predicted directions. Grouping had adverse effects on nonsense shape recall. Letter recall was better and was facilitated by grouping, except by subjects with poor letter recall spans who were also slow at letter naming. Mental and chronological age were associated with higher scores, but unlike set size, did not relate differentially to letter grouping. It was argued that the form of coding is a factor in determining the nature of processing and in recall efficiency.

Blindness↗

PubMed1979

Generation of cytolytic T lymphocytes in vitro. X. Induction of primary and secondary CTL responses by the mitogen sodium periodate.

Short-term (15 min) sodium periodate (NaIO4) treatment of mouse spleen cells previously primed in vivo or in vitro against alloantigens induced the formation of secondary (2 degree) cytolytic T lymphocytes (CTL) specific for the priming antigens. CTL formation was readily demonstrable within 24 hr after treatment. This early CTL response occurred equally well in the presence or absence of cytosine arabinoside (Ara C), indicating that NaIO4 could induce CTL independently of DNA synthesis. Forty-eight hours after periodate treatment, the lytic activity was similar to that observed in parallel cultures stimulated with irradiated allogeneic spleen cells, although the peak activity was reached earlier (day 4) and was somewhat lower than that induced by alloantigen. The addition of irradiated NaIO4-treated unprimed syngeneic spleen cells to cultures of untreated alloimmune spleen cells also led to CTL formation, which suggests an indirect mechanism of activation. In contrast to alloimmune spleen cells, normal spleen cells treated with NaIO4 developed only very low levels of cytotoxicity after 4 days of incubation. However, in the presence of PHA, such cells were capable of lysing syngeneic and allogeneic target cells.

Animals↗

PubMed1976

Antigenic specificity of the cytolytic T lymphocyte (CTL) response to murine sarcoma virus-induced tumors. I. Preferential reactivity of in vitro generated secondary CTL with syngeneic tumor cells.

Incubation of spleen cells from mice having rejected a Moloney sarcoma virus (MSV)-induced tumor with syngeneic irradiated lymphoma or sarcoma cells bearing MSV-associated antigens in secondary mixed leukocyte-tumor cell cultures (MLTC) resulted in the generation of highly active cytolytic T lymphocytes (CTL) specifically directed against syngeneic target cells bearing MSV-associated antigens. When MSV-immune spleen cells from C57BL/6 (H-2b) and BALB/c(H-2d) mice were compared with respect to their ability to generate CTL in syngeneic secondary MLTC, it was found that both lymphoid cell populations were equally able to mount an anamnestic CTL response to MSV-associated antigens as assessed by a short-term 21Cr release assay. However, quantitative analysis of the activity of both CTL populations on either H-2b or H-2d tumor cells indicated that target cells sharing the same major histocompatibility complex (MHC) as the effector cells were lysed 10- to 100-fold more efficiently than allogeneic target cells. As suggested by the results of inhibition experiments using mixtures of 51Cr-labeled and unlabeled target cells, preferential lysis of syngeneic versus allogeneic tumor cells might be related to the establishment of effective adhesions between the former and CTL. Direct evidence for the role of MHC in determining the antigenic specificity of CTL directed against MSV-associated antigens was provided by results obtained using MSV-immune spleen cells from congenic resistant mice. Furthermore, studies of the response of F1 (H-2b/d) hybrid mice showed that stimulation of immune spleen cells with tumor cells from one parental strain or the other in secondary MLTC resulted in the generation of CTL capable of lysing tumor target cells of the same perental strain as the stimulating cells, but not of the other. The results thus suggested the presence of two sets of CTL precursor cells in F1 MSV-immune spleens, each set responding exclusively to tumor antigens associated with only one of the two parental phenotypes.

Animals↗

PubMed1977

Passive transfer of systemic tumor immunity with cells generated in vitro by a secondary immune response to a syngeneic rat gross virus-induced lymphoma.

Spleen cells taken from W/Fu rats 4 to 6 weeks after immunization with the syngeneic Gross virus-induced lymphoma, (C58NT)D cells, at a time when they lack detectable activity in a short-term 51Cr release assay, were previously shown to retain the capacity to generate cytotoxic activity upon reexposure to mitomycin C-treated lymphoma (C58NT)D cells in vitro. In the studies presented here, we evaluated whether in vitro sensitization of immune lymphoid cells before systemic transfer to a nonimmune recipient allows for more effective transfer of tumor immunity. The results show that the passive transfer of immune spleen cells after in vitro cocultivation with mitomycin-treated (C58NT)D cells allows for inhibition of growth of a subcutaneous inoculum of lymphoma cells. In contrast, spleen cells obtained 4 to 6 weeks after primary sensitization or after secondary in vivo sensitization did not effectively confer anti-tumor immunity. As few as 5 x 107 in vitro sensitized cells permitted complete inhibition of 106 (C58NT)D cells and also allowed for inhibition of the growth of 107 (C58NT)D-F cells, which was lethal to control animals. Immune cells sensitized with syngeneic thymocytes or normal spleen cells sensitized with (C58NT)D cells in vitro did not confer in vivo anti-tumor immunity. After systemic transfer of in vitro sensitized cells, delayed hypersensitivity occurred at the site of tumor inoculation and tumor growth was suppressed. Specificity of the passive immunity was shown by the failure to inhibit growth of a polyoma virus-induced sarcoma in rats which inhibited growth of the Gross virus-induced lymphoma cells. In vitro sensitized cells were more effective in the transfer of anti-tumor protection after 5 days, as compared to 2 days, of cocultivation with tumor. Results show that in vitro sensitized cells can effectively transfer systemic tumor immunity.

AKR murine leukemia virus↗

PubMed1992

"Live" neuron and optimal learning rule.

A concept of the live unit as an automatic regulation system with a few admissible states areas in the space of states is considered. Energetic profit of oscillatory behavior consisting in the consecutive transitions of system from one admissible states area to another is shown. It is stated, that external disturbances cause the energy consumption of oscillatory system to decrease. On the basis of this concept and some neurophysiological data, the "live" energy-consuming nonlinear three-state neuron model is proposed and the existence of energy optimal generation frequency v(opt) is proved. For the realization of tendency to v(opt) the optimal learning rule is proposed, which provides unsupervised learning and interlinked short-term and long-term memories with forgetting. The model proposed explains the genesis of neural network, is promising in the sense of network self-organization and allows to solve the problem of internal activity in the researches on artificial intelligence.

Biological Clocks↗

PubMed2025

Intratumoral B cell and interferon signatures in newly diagnosed glioblastoma are associated with longer survival in patients treated with SurVaxM.

Glioblastoma (GBM) has proved difficult to treat, and there is dire need for more effective therapies. In a single arm phase IIa trial (NCT02455557), treatment of newly diagnosed GBM patients with the peptide vaccine SurVaxM resulted in promising median progression-free and overall survival. To investigate molecular features that associate with GBM responsiveness to SurVaxM, retrospective whole exome and RNA sequencing was performed on patient tumors (n = 34) collected prior to standard of care treatment plus SurVaxM. Differential gene expression and mutational profiles were characterized between patients with short-term (OS < 18 months) or long-term (OS ≥ 18 months) overall survival. Greater expression of interferon, complement, and humoral immunity signatures were associated with long-term survival. Deconvolution of transcriptomes identified enrichment of intratumoral memory B cell populations in long-term survivors that were validated by CD20 staining in matched samples. A five-gene expression signature and a B cell specific signature predicted survival within the SurVaxM-treated cohort, however, these signatures were not associated with improved outcomes in a similarly treated population obtained from The Cancer Genome Atlas (TCGA) that did not receive immunotherapeutic intervention. Although prospective validation is ongoing, the findings in this discovery cohort specify molecular features of GBM associated with better overall survival and potential responsiveness to immunotherapy with SurVaxM.

Humans↗

PubMed1991

Spatial performance correlates with in vitro potentiation in young and aged Fischer 344 rats.

Young adult (2-4 months old) and aged (24-26 months old) Fischer 344 (F344) rats were trained for spatial behavior (locating a hidden escape platform) in a circular water maze. The aged rats showed deficits in both the acquisition and retention of the learned response. Following the behavioral training, hippocampal slices from the rats were prepared. Potentiation of CA1 extracellular, somatic field potentials was studied in vitro following either a short stimulus train (4 pulses) or a longer train (50 pulses). Slices from the aged rats showed less short-term potentiation (124.8 +/- 4.9% baseline, mean +/- S.E.M.) at 1 min following the short train in comparison to slices from the young rats (151.8 +/- 7.5%, P less than 0.05). However, following the longer train, no differences were found between the groups in the degree of either short-term (measured at 1 min after stimulation) or long-term potentiation (measured at 60 min). The amount of potentiation seen at various time points after either train correlated with the behavioral measure of retention. These results indicate that F344 rats exhibit age-related behavioral deficits, and age-related synaptic potentiation deficits in response to short stimulation trains. The correlation between the degree of potentiation (both short-term and long-term) and retention of a behavioral task adds strength to the hypothesis that potentiation mechanisms may underlie memory processes.

Aging↗

PubMed1992

Cytokines in neuroinflammatory disease: role of myelin autoreactive T cell production of interferon-gamma.

Many cytokines must be considered as effector and immunoregulatory molecules in neuroinflammatory diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). We have studied the potential role of interferon-gamma (IFN-gamma) in the pathogenesis of these diseases, since this cytokine has a number of important effects such as macrophage activation, induction of MHC class I and class I antigens, and T cell homing. An immunospot assay that allows enumeration of single cells secreting IFN-gamma after short-term culture in vitro of mononuclear cell suspensions has been used. In EAE, increased numbers of IFN-gamma-secreting cells (IFN-gamma-sc) appear in the central nervous system shortly before onset of clinical signs. Such cells also increased during pharmacologically induced relapse of EAE. In later stages of EAE, memory T cells that produced IFN-gamma in response to presented antigen, recognized multiple regions of the myelin basic protein (MBP), showing that (i) myelin autoreactive T cells have the functional ability to produce this cytokine, (ii) the concept of immunodominance as to autoantigen peptide reactivity is non-absolute and time-dependent. In multiple sclerosis (MS) there are increased numbers of IFN-gamma-sc among the CSF cells. Also, there are increased numbers of memory T cells, strongly enriched to the cerebrospinal fluid, which upon recognition of several myelin antigens and several MBP peptide stretches, produce IFN-gamma. Taken together, the data are consistent with a role for IFN-gamma as a key mediator in inflammatory demyelinating diseases.

Animals↗

PubMed1992

Synaptic enhancement induced by NMDA and Qp receptors and presynaptic activity.

Activity-dependent changes in synaptic efficacy may underlie the acquisition of memory. Much interest has centred on the involvement of NMDA (N-methyl-D-aspartate) receptors in the induction of long-term potentiation (LTP), but since activation of this receptor alone results only in short-term enhancement, other receptors are clearly involved. This paper describes a novel form of lasting synaptic enhancement requiring concomitant activation of both NMDA and metabotropic quisqualate, or Qp receptors for induction. Neither high frequency presynaptic activity, co-activation of many presynaptic axons, postsynaptic depolarization, nor blockade of inhibition were required. However, repetitive, though relatively low frequency activity of the presynaptic axon appeared to be necessary. We suggest, tentatively, that presynaptic activity may be directly involved in priming the recently active terminal to respond to postsynaptic changes.

Animals↗

PubMed1991

Identification of cyclic AMP as the response regulator for neurosecretory potentiation: a memory model system.

The neural cell line HT4 serves as a model for memory by exhibiting short- and long-term potentiation of neurotransmitter secretion. Previous studies showed that membrane depolarization elicits secretion and that serotonin and N-methyl-D-aspartate receptors are involved in potentiation of the response. Adrenergic and adenosine receptors, which are coupled to adenylate cyclase, are also found to induce potentiation. In addition, the direct evaluation of cAMP levels by forskolin, or by addition of dibutyryl cAMP, induces potentiation. In these different types of stimuli, it is the level of cAMP that is the common factor allowing prediction of whether potentiation will be observed or not. The cAMP level therefore qualifies as the response regulator for this phenomenon. Repetitive adrenergic receptor stimulation results in short-term potentiation, while repetitive adenosine stimulation results in long-term potentiation. This difference can be explained by assuming that some precursor that determines the cAMP level exceeds a threshold, to produce long-term potentiation. This threshold is exceeded by adenosine stimulation but not by stimulation of the beta-adrenergic receptor.

Adenosine↗

PubMed1979

Short-term recall of nine-digit strings and the EEG.

In three exploratory studies, EEG changes were monitored while subjects performed a nine-digit recall task. Experiment 1 involved auditory presentation without practice or prior instruction. EEG characteristics measured before the task related to subsequent recall, EEG activation increased progressively during digit presentation and rehearsal, and several between- and within-subject analyses showed increased activation to be associated with poor recall performance. In Expt. 2 the digits were presented visually and subjects were given instruction and practice in an efficient rehearsal strategy. Recall performance improved but its relationship with the pre-task EEG disappeared. Activation increased with digit presentation but the relationship between the EEG and performance was complex since a within-subject analysis associated decreased activation with better performance (as in Expt. 1) while this relationship was reversed in a between-subject analysis. The results are explained both in terms of traditional findings relating activation to recall, and drive theory accounts of learning and performance. Finally, Expt. 3 demonstrated that performance was better, both in the morning (compared with the evening) and on a second testing session. There were complex time of day effects for the EEG, with lower and higher measured frequencies yielding higher voltage output in the evening and intermediate frequencies showing a reverse effect. In summarizing the data from the three experiments it is suggested that different EEG frequencies are differentially sensitive to different conditions (task specific factors, stimulus input characteristics, knowledge of success and failure, degree of task mastery and circadian variation).

Arousal↗

PubMed1992

Short-term retention of spatial information.

Four experiments investigated the recall of a subspan set of spatial locations over short intervals of 5 and 15 s. The intervals were filled by one of three activities: simple tapping, repeated tapping at spatial targets and backwards counting. Spatial tapping, which decreases spatial memory span, led to further small but significant errors in recall, as did backward counting. These errors were larger than those found with simple tapping over the same intervals. Backwards counting led to further decreases in recall performance if it was also present during encoding, but this was not the case for spatial tapping. Spatial tapping had little effect on recall of three digits, whereas backwards counting had a large effect, which was much larger than that found with spatial memory items in any condition. The results are interpreted in terms of the use of place-keeping functions in spatial memory sequences, which may not be specific to spatial material.

Female↗

PubMed1978

Perceptions of movement patterns: recall of movement.

The present study attempted to characterize the perception retention, and recall of kinaesthetic information regarding movement sequences (patterns). An attempt was made to draw on and extend conclusions relevant to simple movements (movement amplitude). One group of 10 blindfolded subjects recalled criterion movement patterns that had been actively commanded and 10 subjects recalled passively induced movements. The following conclusions were made. (1) Previous reports of algebraic errors in the recall of simple movement amplitudes are consistency with the finding that criterion perimeter, area, and depth of features were underestimated when recalled. (2) Measures of the accuracy of kinaesthetic perception do not alone account for the generally low level of pattern recall, the large range of individual differences or the underestimation of amplitude. The process of percept formation and of translating a percept into recalled movement are implicated. (3) Conclusions based on the short-term retention and recall of simple movements do not account for the coding, retention, and recall of movement sequences (patterns). (4) Percepts were formed, and patterns were recalled as a sequence of features but not as a sequence of key positions. (5) No direct difference was demonstrated between the recall of actively commanded and passively induced criterion movement patterns. However, the finding of a high gross angle change in the active condition was explained in terms of an unfavourable interaction between corollary discharge and sensory information.

Female↗

PubMed1975

[In vitro comparison of 2 expressions of cellular immunity induced by a cutaneous allograft in the mouse].

A short-term test (5 h) has been compared to a long-term test (48 h) for evaluation of the cellular cytotoxic response which is induced in recipients of allografts. Spleen cells from mice recipients of skin allografts were tested. We have shown that the cellular cytotoxicity expressed in a short-term test is itself expressed during a short period whereas the cytotoxicity expressed in a long-term test is still detectable for months after a first skin graft. Moreover, the lytic activity of the spleen cells is much higher when it is expressed in a long-term test. The fact that we could get, in vitro, in two days, a low primary cellular cytotoxic response against alloantigens, makes likely that during the long-term test, the anamnestic response which can develop is especially responsible for the cellular cytotoxic response.

Animals↗

PubMed1991

Effects of (DesGly9-Arg8) vasopressin on cognitive processes in alcoholic patients.

The effect of intranasally administered (DesGly9-Arg8) vasopressin (DGAVP) on certain aspects of cognitive functions of alcoholic patients was studied. The investigation was carried out in 103 chronic alcoholic patients. None of the patients suffered from Korsakoff's syndrome, portal encephalopathy or brain damage of other etiology. The trial was double-blind, placebo controlled. Psychological testing, which included certain aspects of attention, short-term and long-term memory and spatial orientation, was carried out on the day before (baseline measurements), on the last day (II), and seven days after the last administration of DGAVP (III). No treatment effect of DGAVP was observed. The results show that investigations with humans are infinitely more complex than those with animals, since a number of physiological and socio-psychological factors must be controlled. In this study of alcoholics two such factors: 1) duration of abstinence and 2) adaptation to test situation were identified.

Adult↗