Investigations on integration of mossy fiber inputs to Purkyně cells in the anterior lobe

Summary The 275 Purkyn cells identified by the criteria of the previous paper have been investigated with respect to their role as units integrating the input to the anterior lobe from various limb nerves. The discharges from single Purkyn cells have been studied in lightly anesthetized (pentothal) or in decerebrate unanesthetized cats, there being averaging usually of 128 responses in the form of post-stimulus time histograms and cumulative frequency distributions.Single Purkyn cells exhibited a wide variation in their responses to the diverse inputs from the various afferent nerves. Attention was focussed on excitatory and inhibitory responses evoked by mossy fibers with a short latency, usually 10–15 msec for hindlimb afferents. With most Purkyn cells these responses were predominantly evoked from cutaneous nerves, low threshold fibers being particularly effective. A few Purkyn cells were preponderantly excited by afferent volleys from muscle nerves, but there was a large group with a mixed input from cutaneous and muscle nerves. Graded strengths of stimulation of muscle nerves showed that sometimes group I volleys were prepotent, but other Purkyn cells were selectively excited by group II volleys. Though sometimes the afferent volleys from antagonistic muscles had a reciprocal action on a Purkyn cell, as on a motoneurone, it was more common to find similar actions. Also convergence of inputs from forelimb and hindlirnb nerves, both cutaneous and muscular, was not uncommon, particularly in marginal areas between hindlimb and forelimb zones. A special design feature is the convergence onto a Purkyn cell of mossy fiber and climbing fiber inputs evoked by the same afferent volley. This convergence was of particular interest along the parasagittal strip of hindlimb climbing fiber distribution in lobule V.It was not possible to translate the observations into some map of the cerebellar cortex on which are marked the territorial distributions from the various limb afferent nerves. Rather, there was an ill-defined patchy character, closely adjacent Purkyn cells often receiving very different subsets of the total input from the various limb nerves. The unitary integrations accomplished by the individual Purkyn cells are further integrated when their axons converge onto and inhibit the neurones of the cerebellar nuclei, and this integration by convergence would occur in each successive relay on the output pathways from the cerebellum.It is pointed out that the experimental findings on the integrative action of the individual Purkyn cells provide basic information for attempts to construct models simulating cerebellar performance and control.Post-Doctoral Fellow NINDS (1F2NB40, 545101 NSRB).Post-Doctoral Fellow UHF Grant No. FTF-3-UB-70.     

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis - acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.      

Afferent volleys in limb nerves influencing impulse discharges in cerebellar cortex I. In mossy fibers and granule cells

Summary This paper is the first of a series in which the processing of information in the cerebellum has been studied by investigating the effects that known inputs from limb nerves produce on the unitary spike potentials in the cerebellar cortex. These spikes have been recorded extracellularly at all depths along microelectrode tracks in the 5th, 4th and 3rd lobules of the anterior lobe in the lateral vermis or in the pars intermedia. These units have a background frequency of discharge, often very irregular, and computer averaging techniques have been employed in order to derive reliable information on the time course and intensity of the excitatory and/or inhibitory actions produced by the input against this background.Most of the spike responses recorded from the granular layer fall into two classes, one characteristic of impulses in mossy fibers, and the other of impulse discharges from granule cells. Both in the spontaneous background and in the response to afferent volleys in limb nerves the mossy fibers exhibit a performance in close accord with that described for the discharges up the spino-cerebellar tracts. The short latency of 6–9 msec for hindlimb stimuli and the high frequency burst response of 2–4 impulses are characteristic. The mossy fibers displayed a wide variety of responses to the wide range of testing inputs, there being various combinations of excitatory and inhibitory responses and also delayed excitatory actions, all of which must be assumed to be reflections of synaptic influences on the cells of origin of the mossy fibers in the spinal cord.Granule cells have a longer latency by several milliseconds, 9–20 msec for the hindlimb, and a slower frequency in their burst response which tended to be longer and more irregular. The small unitary spike potentials are more difficult to isolate. Also with repetitive stimulation granule cells are more readily depressed than are mossy fibers.Usually a granule cell exhibits a wider range of response to the various cutaneous and muscular afferents of a limb. Both mossy fibers and granule cells may display reciprocal responses to volleys from muscle nerves to antagonistic muscles. This attempt to define properties of the mossy fiber and granule cell spike potentials should help in their identification in future investigations.Post-Doctoral Fellow NINDS (1F2NB40,544101 NSRB).Post-Doctoral Fellow UHF Grant No. FTF-3-UB-70.     

Influences on prescribing in non-fundholding general practices.

BACKGROUND: The experience from general practice fundholding suggests that financial incentives may influence prescribing; guidelines and hospital prescribing are two other suggested influences. AIM: A study was undertaken to establish general practitioners' attitudes to a financial prescribing incentive scheme, the presence and use of guidelines, and the influence of prescribing initiated within secondary care. METHOD: A postal questionnaire survey of non-fundholding general practices in the former Northern Region was conducted. RESULTS: Practices' thinking and subsequent decisions about the incentive prescribing scheme were most often influenced by discussions within the practice (45%). Those practices that achieved their savings under the incentive scheme were less likely than those not achieving savings to feel that the target was not achievable, the time scale was unacceptable, and that the philosophy behind the scheme was unacceptable. Forty-five per cent of practices received advice from neither a medical nor a pharmaceutical adviser; 27% of practices received advice from both, 12% from a medical adviser only and 16% from a pharmaceutical adviser only. Of the practices that tried to make their target savings, 91% intended to increase generic prescribing; fewer than one-third of practices mentioned any other measure. Prescribing guidelines were reported by a minority of practices, although reported rates of use were high when these were present. Clinical guidelines for three conditions, asthma, diabetes and hypertension, were present in more than 50% of practices; 25% of practices had no clinical guidelines. Hospital prescribing was reported as 'always' or 'usually' influencing prescribing for diabetes by 57% of respondents, ischaemic heart disease by 55%, peptic ulceration by 49%, asthma by 42% and hypertension by 39%. CONCLUSIONS: General practitioner prescribing is influenced by a complex web of factors, with no single factor pre-eminent. To understand this area further, there is a need to take each of these areas and ascertain the match between doctors' perceptions and actual practice.     

Topographic studies on medial reticular nucleus.

Several distinct classes of neurons have been identified in the medial reticular nucleus of the medulla and pons and in proximity thereto. Neurons projecting down the spinal cord comprised the principal class with two subclasses according as the neurons did or did not receive monosynaptic inputs from the fastigial nuclei of the cerebellum. Two other classes were recognized accordings as they projected to the cerebellum or rostrally to the mesencephalon. Topographic planar maps giving the location of these neurons have been constructed by exploring the nucleus with series of microelectrode tracks in parasagittal or in transverse planes. The different classes of neurons were not arranged in large discrete nuclei. In part they appeared to be randomly distributed, but many colonies of one or another class of neurons could be recognized with 3-11 neurons in zones with dimensions of a millimeter or so. Because of the limitations of sampling by microelectrode tracks at spacings of 0.5 mm, single colonies might have an actual population of 100 or more. Many of the class of neurons projecting to the cerebellum were in the region of the perihypoglossal nucleus. However, almost as many were located deep in the medial reticular nucleus. None was found at the pontine level. Reticulospinal neurons with fast axonal conduction velocities tended to be located dorsally to those with slow velocities. Correlation with the findings of Ito et al. leads to the conjecture that the neurons with fast axons are excitatory, while those with slow axons are primary inhibitory neurons. There is a brief reference to the problems raised by the admixture of the various neuronal classes, there being discrete colonies immersed in a scattered arrangement of all classes.     

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.

     

A framework for incorporating cost-effectiveness in evidence-based clinical practice guidelines.

In England, recent health care reforms emphasise the role of clinical guidelines in promoting effective and efficient health care. Introducing economic data into guidelines raises some methodological issues: specifically, the provision of valid and generalisable cost estimates, the weight placed upon cost 'evidence', and the presentation of cost-effectiveness information in a manner accessible to clinicians. A series of primary care guidelines, explicitly including consideration of health economic information, have recently been published, intended to help clinicians to aggregate the attributes of treatment choices to derive treatment recommendations consistent with both the clinical decision-making process and social objectives. Clinicians involved in developing guidelines responded well to the process and consistently managed to agree treatment recommendations, often after considerable debate about the evidence for treatment. In none of the guideline areas, all of which addressed common diseases, was there adequate information to estimate a cost per quality-adjusted-life-year, and it is unclear how helpful this approach would have been had it been possible. The implications of this method are discussed, guidance offered for economists new to guideline development and future areas of work identified.