Calcium in long-term potentiation as a model for memory

The granule, CA1 and CA3 cells of the hippocampus have been much investigated during the last decade because there is superimposed on the standard features of synaptic transmission a very prolonged potentiation lasting for weeks that is called long-term potentiation. Evidently long-term potentiation is a promising candidate in the construction of a model for memory. The thesis here developed is that the influx of calcium ions across the membrane of the granule and pyramidal cells plays the key role in the generation of long-term potentiation. This proposal makes it possible to account for the necessity of strong repetitive synaptic stimulation, preferably in bursts so as to optimize the conditions for the calcium influx. Studies on hippocampal slices with variations in the synaptic inputs to the granule cells give evidence of cooperativity, which is interpreted in relation to the threshold membrane depolarization for calcium influx. It is conjectured that the large increase of calcium in the granule and pyramidal cells results in its combination with the specific protein, calmodulin, to form a second messenger system, which produces metabolic changes leading to an increase in receptors of the postsynaptic membrane of the spine synapses, i.e. the postsynaptic densities, to the synaptic transmitter, glutamate. For example, Ca²⁺ could activate calcium-dependent kinases in the postsynaptic density resulting in the modification of protein components by phosphorylation. Other postsynaptic factors contributing to long-term potentiation are presumed to be protein synthesis with spine swelling and increased transport up the dendritic microtubules.

There is discussion of the evidence for the alternative hypothesis that long-term potentiation is primarily presynaptic, being due to an increased output of transmitter. A unifying hypothesis is formulated, namely, that the primary event in long-term potentiation is in the increased sensitivity of the postsynaptic densities to the transmitter, and that, secondarily, this induces an increased output of transmitter from the presynaptic terminals by a trophic action across the synaptic cleft.

It is shown how the proposed combination of calcium with calmodulin will account for the hypothesis of Marr that cognitive memory is due to conjunction potentiation. Furthermore, the Marr-Albus hypothesis for cerebellar learning is accounted for if the calcium-calmodulin messenger system causes the observed depression of the transmitter sensitivity of the spine synapses on Purkyneˇcells.     

Intraparenchymal pulmonary lymph node: case report and literature review

Summary A case of a 44-year-old woman with a solitary pulmonary coin lesion is presented. Histologic study of this nodule revealed a normal intraparenchymal pulmonary lymph node. A review of the literature discusses the incidence and characteristics of this entity.

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Nud lymphatique intrapulmonaire: revue de la littérature. A propos d'un cas

Résumé L'observation d'un cas de lésion nodulaire du poumon est rapportée chez une femme de 44 ans. L'étude histologique du nodule a révélé un nud lymphatique intrapulmonaire normal. La revue de la littérature apprécie l'incidence et les caractéristiques de cette localisation.

     

The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.      

Innovation and restrictive conformity among hospital employees: individual outcomes and organizational considerations

Two factors characterize innovative organizational climates as perceived by nonmanagerial hospital employees. The first, innovation, comprises perceptions about the consequences or contingencies (e.g., punished, ignored, rewarded) of such proactive activities as implementing new ideas, questioning established methods, and communicating with other departments and the supervisor. The second, restrictive conformity, comprises perceptions about the consequences of risk-aversive, conflict-avoidant activities that suggest dysfunctional conformity (e.g., "sticking to the rules no matter what"). Positive personal outcomes--greater role clarity, organizational involvement, and satisfaction, and lower role conflict and willingness to leave the organization--are associated with innovation; negative personal outcomes are associated with restrictive conformity. The dialectical tension between conformity and innovation is discussed in terms of loose coupling and a reward systems perspective.     

Incorporating economic analysis in evidence-based guidelines for mental health: the profile approach

BACKGROUND: Many western health systems are currently developing the role of clinical guidelines to promote effective and efficient health care. However, introducing economic data into guideline methodology designed to assess the effectiveness of interventions raises some methodological issues. These include providing valid and generalizable cost estimates, the weight placed upon cost "evidence" and presenting cost-effectiveness information in a way that is helpful to clinicians. AIM OF THE STUDY: To explore a framework for including economic concepts in the development of a series of primary care guidelines, two of which address mental health conditions. METHODS: A profile approach, setting out best available evidence about the attributes of treatment choices (effectiveness, tolerability, safety, health service delivery, quality of life, resource use and cost), was used to help clinicians to derive treatment recommendations in a manner consistent with both the clinical decision-making process and social objectives. RESULTS: Clinicians involved in guideline development responded well to the process. Although there was often considerable debate about the meaning and importance of different aspects of evidence about treatment, in none of the guideline groups was there failure to agree treatment recommendations. DISCUSSION: The profile approach may be particularly useful in the field of mental health where disease processes may often feature very disparate effects, over long periods of time and impacting upon a broad circle of relatives, carers and agencies in addition to the patients themselves. CONCLUSION: A method has been applied in a series of primary care guidelines, which appears to enable clinicians to consider the issue of resource use alongside the various clinical attributes associated with treatment decisions. The basis of this work is the belief that guidance presenting physical measures describing effectiveness, adverse events, safety, compliance and quality of life, alongside resource consequences, is most likely to appropriately inform doctor-patient interactions. IMPLICATIONS FOR HEALTH CARE PROVISON AND USE: This research may provide a useful platform for other groups considering how to introduce cost-effectiveness concepts into guideline development groups. Whether guidelines change clinical behaviour remains a research question, and the subject of forthcoming trials. IMPLICATIONS FOR HEALTH POLICY FORMULATION: It is important that government agencies realize that guideline development is a health policy tool with prescribed methods to produce valid guidelines. Attempts to tamper with the methodology for cost-containment purposes or other political reasons are likely to discredit a useful mechanism for improving the scientific basis of health care provision. IMPLICATIONS FOR FURTHER RESEARCH: There are a number of limitations to completed work: for example it has a primary care focus and addresses fairly narrowly defined conditions. Work is ongoing to extend the scope to broader disease areas and to secondary care.     

Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligands

Evidence suggests that there is an association between the abnormal expression of members of the c-erbB receptor tyrosine kinase family and poor prognosis in head and neck squamous cell carcinomas (HNSCC). Until now, the relative contributions of different c-erbB ligands to HNSCC progression have not been clearly defined. In this paper we examined the effects of ligands with different c-erbB receptor specificities in terms of their stimulation of HNSCC proliferation, expression of matrix metalloproteinases (MMPs) and invasion. Heregulin-beta1 (HRG-β1; selective c-erbB3/B4 ligand) was found to stimulate proliferation in the majority of cell lines, whereas epidermal growth factor (EGF; EGFR ligand) and betacellulin (BTC; EGFR/B4 ligand) induced variable responses. All three ligands up-regulated multiple MMPs including collagenases, stromelysins, matrilysin and gelatinase B (MMP-9) but had minimal or no effects on gelatinase A (MMP-2), MT1-MMP and tissue inhibitors of MMPs (TIMPs). MMP-9 mRNA was induced to a higher level than other MMPs, although with slower kinetics. HRG-β1 was less active than EGF and BTC at the optimal concentration (relative potency of EGF:BTC:HRG = 3:4:1). In vitro invasion through Matrigel was also increased by all three ligands in proportion to their MMP up-regulation. A specific anti-EGFR monoclonal antibody (mAb ICR62) inhibited MMP up-regulation, migration and invasion induced by all three ligands, whereas an anti-c-erbB-2 mAb ICR12 inhibited mitogenic and motogenic responses following ligand stimulation but had no effect on MMP expression. These results suggest that c-erbB ligands may differentially potentiate the invasive phenotype of HNSCC via co-operative induction of cell proliferation, migration and proteolysis. The EGFR signalling pathway appears to be the dominant component controlling the proteolytic and invasive phenotype in HNSCC, whereas the c-erbB-2 signalling pathway is responsible, in part, for the mitogenic and motogenic effects of ligands. This revised version was published online in July 2006 with corrections to the Cover Date.