Perioperative assessment of older surgical patients using a frailty index-feasibility and association with adverse post-operative outcomes.

This study aimed to examine the feasibility of using a frailty index (FI) based on comprehensive geriatric assessment (CGA), to assess the level of frailty in older surgical patients preoperatively and to evaluate the association of FI-CGA with poorer postoperative outcomes. Two hundred and forty-six patients aged ≥70 years undergoing intermediate- to high-risk surgery in a tertiary hospital were recruited. Frailty was assessed using a 57-item FI-CGA form, with fit, intermediate frail, and frail patients defined as FI ≤0.25, >0.25 to 0.4, and >0.4, respectively. Adverse outcomes were ascertained at 30 days and 12 months post-surgery. Logistic regression models assessed the relationship between FI and adverse outcomes, adjusting for age, gender and acuity of surgery. The mean age of the participants was 79 years (standard deviation [SD] 6.5%), 52% were female, 91% were admitted from the community, 43% underwent acute surgery, and 19% were assessed as frail. The FI-CGA form was reported as being easy to apply, with a low patient refusal rate (2.2%). The majority of items were easy to rate, although inter-rater reliability was not tested. In relation to outcomes, greater frailty was associated with increased 12-month mortality (6.4%, 15.6%, and 23% for fit, intermediate frail, and frail patients respectively, P=0.01) and 12-month hospital readmissions (33.9%, 48.9%, and 60% respectively, P=0.004). There were no statistically significant differences between fit, intermediate frail, and frail groups in perioperative adverse events (17.4%, 23.3%, and 19.1% respectively, P=0.577) or 30-day postoperative complications (35.8%, 47.8%, and 46.8% respectively, P=0.183). Our findings suggest that it is feasible to use the FI-CGA to assess frailty preoperatively, and that using the FI-CGA may identify patients at high risk of adverse long-term outcomes.

Prelabeled red nucleus and sensorimotor cortex neurons of the rat survive 10 and 20 weeks after spinal cord transection.

To demonstrate definitively the fate of the somata of rubrospinal and corticospinal neurons axotomized by a complete spinal cord transection at T-9, in young adult rats we prelabeled the neurons by injection into the lumbar enlargement of a retrogradely transported fluorescent dye, Fluoro-Gold, and four days later transected the cord. We found no loss in cell number ten or 20 weeks after axotomy. The average size of the neurons in each case is slightly but significantly reduced. These findings unequivocally demonstrate that the somata of long tract neurons of the rubrospinal and corticospinal systems persist in an atrophic and presumably inactive state for at least 20 weeks, and raise the possibility that treatment of spinal cord injury may normalize cell activity and allow long tract regeneration.

Changes in number and size of Clarke's column neurons after cord transection.

The number of large neurons in Clarke's column of the L-1 segment of the spinal cord of the rat decreases five or more weeks after a T-9 spinal cord transection. Analysis of cells at 1, 2, 3, 5, 7, 9, 12, and 15 weeks (wk) postoperatively demonstrates a loss of large neurons at each time interval beyond five wk postoperatively. Comparison of cell sizes found in the anatomic region of Clarke's column at two or three wk postoperatively with the cells found at 15 wk after transection and their respective control groups, shows a decrease in total cells found in operated rats 15 wk postoperative with a profound decrease in larger neurons in these rats. We did not detect a significant offsetting increase in smaller neurons. We believe the observed changes are due to death of large neurons and can find no evidence to support the contention that axotomized cells persist in a shrunken, atrophic state.

Organization of afferent connections of the feline lateral habenular nucleus.

The organization of afferent projections to the lateral habenular nucleus (LHB) was studied in adult cats. In autoradiographic experiments, tritiated leucine injections were made into regions shown in retrograde transport studies to project to LHB (lateral hypothalamus, preoptic region, entopeduncular nucleus, and midbrain raphe) to determine the locations of axonal trajectories and terminal zones. The distribution of silver grains in the ipsilateral LHB differed according to the injection site. Entopeduncular nucleus projected to the ventrolateral part, raphe to the dorsomedial part, preoptic region to the central part, anterior hypothalamus to all but the ventrolateral part, and posterior hypothalamus to all but the dorsomedial part. The lateral hypothalamus, preoptic region, and anterior portion of the entopeduncular nucleus projected primarily through the inferior thalamic peduncle and stria medullaris, while the posterior portion of the entopeduncular nucleus projected more diffusely through thalamus to enter LHB from its ventral aspect. Raphe axons reached LHB through the fasciculus retroflexus. Entopeduncular and lateral hypothalamic axons passed through the habenular commissure to the contralateral stria medullaris to reach the contralateral LHB. Silver grains in LHB were distributed similarly bilaterally, but were much less dense contralateral to the injection. The major afferent projections to the feline LHB are therefore topographically organized. The significance of this organization in relation to the possible role of the LHB in integrating limbic and extrapyramidal motor systems is discussed.

Projections of the locus coeruleus and adjacent pontine tegmentum in the cat.

The projections of the locus coeruleus and adjacent pontine tegmentum have been studied using anatomical and physiological methods in the cat. Axonal trajectories were traced using either the Fink-Heimer I method following electrolytic lesions, or the autoradiographic method after injection of tritiated proline into the nucleus. Results with both methods were similar. Axons of locus noeruleus neurons ascended ipsilaterally through the mesencephalon lateral to the medial longitudinal fasiculus, ventrolateral to the central gray. In the caudal diencephalon, the ascending fibers entered the centrum medianum-parafascicular complex where they diverged into two fascicles: a dorsal fascicle which terminated in the intralaminar nuclei of the thalamus, and a ventral fascicle which gave off fibers to the ventrobasal complex and reticular nucleus of the thalamus while continuing centrolaterally into the lateral hypothalamus medial to the internal capsule. Fibers of the ventral fascicle ascended in the lateral hypothalamus and zona incerta and were traced through the preoptic region into the septum. Fibers could not be consistently traced to the cerebral cortex, and were not seen at all in the cerebellum. Throughout the ascending course of the path from the locus coeruleus, axons were given off to the pretectal area, the medial and lateral geniculate nuclei and the amygdala; fibers passed contralaterally through the posterior commissure, the midline thalamus, and the supraoptic commissure. Fibers descending from the locus coeruleus surrounded the intramedullary portion of the facial nerve and further caudally were observed ventrolateral to the hypoglossal and dorsal vagal nuclei. The axonal trajectories visualized with degeneration and autoradiographic methods followed closely those previously shown for reticular formation neurons, but were also similar to locus coeruleus projections revealed by histofluorescence methods. After injections of horseradish peroxidase into the centrum medianum-parafascicular complex, lateral hypothalamus or preoptic region, labeled neurons were located in the locus coeruleus, nucleus subcoeruleus, and lateral parabrachial nucleus. Reticular formation neurons were not labeled. Neurons in locus coeruleus and adjacent pontine tegmentum could be antidromically activated by stimulation in the rostral midbrain or caudal diencephalon. Our data indicate that both adrenergic and non-adrenergic neurons of the dorsolateral pontine tegmentum have similar projections.

The organization of feline entopenduncular nucleus projections: anatomical studies.

The organization of entopeduncular nucleus (EPN) projections was studied in cats using autoradiographic and horseradish peroxidase (HRP) techniques. In autoradiographic studies, EPN axons were found to terminate in a J-shpaed region in the dorsal and medial part of the ventral anterior nucleus (VA) and the rostral portion of the adjacent ventral lateral nucleus (VL). EPN axons also terminated in the rostral portion of the centrum medianum (CM), the ventrolateral portion of the lateral habenular nucleus (LHB), and the pedunculopontine nucleus (PP). The VA included the largest terminal field although the LHB had the greatest density of terminals. Regardless of the region of EPN into which amino acids were injected, the terminal fields were the same: there was no localization within the EPN of the cells projecting to one region. HRP-containing cells were distributed throughout the EPN following injections into the VA, LHB, or PP, although many more cells were labeled following injections into either VA or LHB than PP. EPN cells containing HRP following injections into either VA or LHB were not morphologically different from those not containing HRP in the same respective animals. Following HRP injections into stria medullaris, only cells in the rostral part of the EPN were labeled, providing evidence that rostrally and caudally located EPN neurons have different paths to LHB. Although there may be a rostrocaudal organization of pathways to LHB, individual regions of the nucleus project to the same areas.

Neonatal 6-hydroxydopamine destroys spinal cord noradrenergic axons from the locus coeruleus, but not those from lateral tegmental cell groups.

Subcutaneous injection of 6-hydroxydopamine (6-OHDA) in neonatal rats results in sprouting of collateral axons in locus coeruleus (LC) and lateral tegmental noradrenergic neurons. It has been suggested that this sprouting represents maintenance of neuronal membrane area following "pruning" of axon terminals of long projections to cortex and cord. The chemical or surgical lesions of long axons used to produce "pruning" could also result in the loss of some parent cell bodies. We tested the hypothesis that long axon damage, rather than cell loss, is sufficient to produce collateral sprouting of proximal axons in noradrenergic neurons. With neonatal injections of 6-OHDA at doses which do not produce a loss of LC neurons, there is an 85% decrease in retrograde LC labeling following horseradish peroxidase or true blue injections into the spinal cord but no significant change in the numbers of retrogradely labeled neurons in other noradrenergic cell groups which also sprout collaterals. There is no change in the number of labeled LC neurons following cerebellar injections. In experiments using the fluorescent dyes diamidino yellow and true blue, the number and distribution of LC neurons labeled from spinal cord and cerebellum injections are similar to those in the horseradish peroxidase experiments. Doubly labeled neurons are found in the caudal two-thirds of LC in control rats, but as expected, rarely observed in 6-OHDA-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The organization of projections from the olfactory bulb to the piriform cortex and olfactory tubercle in the rat.

The organization of the projection of olfactory bulb output cells was studied in the rat by injection of horseradish peroxidase (HRP) into the piriform cortex or olfactory tubercle. We made single HRP injections into small cuts in the fiber layer of the projection areas in order to enhance uptake by axons and to confine the region of HRP uptake. Following most of these injections, HRP-labeled axons could be traced in discrete fascicles through the fiber layer of the cortex or tubercle. These observations indicate that axons innervating the piriform cortex do not emit many long collaterals after they leave the lateral olfactory tract. HRP-labeled cells were generally observed throughout the ipsilateral olfactory bulb, but there were regions of greater density of labeled cells that differed in the various brains. The differences among the distributions of labeled mitral and tufted cells were analyzed statistically in 39 brains to test whether they varied systematically with injection site. In these analyses, the olfactory bulb was divided into 30 standard regions, and the labeled cells in each regions were counted. The distributions of labeled cells were similar for brains where injections were made into similar regions of the piriform cortex. The variations in density of labeled cells of the dorsal and anterior regions of the olfactory bulb were most strongly correlated with the positions of cortical injections. In contrast, the posterior medial regions of the bulb were heavily labeled after almost all injections. The ventral portions of the olfactory bulb were most heavily labeled after injections into the olfactory tubercle.

Subcortical structures projecting to visual cortical areas in squirrel monkey.

In 17 adult squirrel monkeys (Saimiri), horseradish peroxidase was used as a retrograde tracer substance to reveal the subcortical structures (other than the lateral geniculate nucleus and pulvinar) which project to the occipital lobe, and, in particular, to the central visual field representation in areas, 17, 18, 19, and MT. Evidence is provided that each of areas 17, 18, and MT receives a projection from locus coeruleus, nucleus dorsalis raphae, nucleus annularis, nucleus centralis superior, formation reticularis pontis oralis, nucleus basalis of Meynert, lateral hypothalamus, claustrum, and nuclei paracentralis and centralis medialis thalami. Area 19 receives a projection from all these structures except from the nucleus annularis. Only area MT was determined to be a target of a projection from the nucleus linearis. For technical reasons, only area MT was determined to receive afferent fibers from the nucleus basalis lateralis amygdalae. The results indicate that there is no topographical organization of subcortical inputs to the central visual field representation in individual cortical areas.

Areal and laminar distribution of neurons interconnecting the central visual cortical areas 17, 18, 19, and MT in squirrel monkey (Saimiri).

The retrogradely transported horseradish peroxidase (HRP) method was used to study the areal and laminar distribution of neurons sending their axons to ipsilateral and contralateral visual cortical areas 17, 18, 19, and MT in the squirrel monkey. Further details regarding neuron type (stellate or pyramidal), size class, and spatial grouping of the cells making these corticocortical connections also were obtained. All interareal connections are reciprocal. Ipsilaterally, such connections exist between areas 17 and 18, 17 and MT, 18 and 19, 18 and MT, and 19 and MT. In addition, areas 18, 19, and MT receive association fibers from the ipsilateral frontal eye field; when combined with previous findings, these results indicate the existence of reciprocal connections between area 18 and the frontal eye field and between area MT and the frontal eye field. Each of areas 18, 19, and MT. Area 17 has only weak callosal connections. Both the ipsilateral and the contralateral connections are topographically organized such that they obey a hodological principle of visuotopic connectivity: that is, only representations of the same part of the visual field are interconnected. With regard to layers of origin, the callosal neurons of these visual areas conform to the general concept of corticocortical fibers arising from supragranular layers in that most of them are located in layer IIIb; only a few of them reside at the junction between layers V and VI. On the other hand, for all the visuocortical connections investigated, the anteriormost area of a reciprocally interconnected pair has its association neurons located predominantly in the infragranular layers while the posteriormost area has its association neurons located primarily in layer III. All callosal fibers and most association fibers arise from pyramidal cells. The callosal cells are larger and reside at a deeper level in layer III than neurons with ipsilateral corticocortical connections. However, some of the association cells at the junction of layers V and VI in area 17 which project to area MT are relatively large and may include the solitary cells of Meynert; but medium-sized pyramidal cells also participate in this projection. In area 17, some association neurons in layers IIIb and IIIc which project to area 18, as well as some in layer IIIc which project to area MT, are most likely stellate cells. Several different patterns of cell groupings were observed for the central representation interconnections. Neither ipsilateral area MT nor any of the contralateral visuocortical areas had multiple groupings of labeled neurons. The ipsilateral projections from area 17 to 18, 17 to MT, and 18 to 19 were arranged similarly according to a plan involving separate, multiple loci of origin for cells projecting to a small and isolated subregion of the central representation in the target cortical area; following larger injections, cells throughout the central representation of the projecting cortex were labeled...

Corticospinal axons persist in cervical and high thoracic regions 10 weeks after a T-9 spinal cord transection.

Ten weeks after complete spinal cord transection at T-9, there was a decrease in the volume of the rat corticospinal tract but no loss in the number of axons contained in the cervical (C-2) or high thoracic (T-1) corticospinal tract. The mean area of the myelinated axon profile decreased in spinal cord-transected rats, with fewer axons found in the largest size groups and more in the smaller size groups. The survival of corticospinal axons in the cervical and thoracic cord 10 weeks after cord transection at T-9 indicates that the corticospinal neurons survive at least 10 weeks after cord transection. The fate of axotomized neurons after longer survival times remains to be determined.

Chronic spinal cord transection does not affect peripheral nerve regeneration.

Spinal cord transection is known to cause progressive changes in motor neurons and hind limb muscles. In the present study, regeneration of the peroneal nerve was examined in rats 25 weeks after a T9 spinal cord transection. Successful regeneration and innervation of the target muscle was observed after crush injury to the nerve in the spinal cord transected animals. It is concluded that the ability of peripheral nerve to regenerate remains preserved after spinal cord injury.

Noradrenergic hyperinnervation of the trigeminal sensory nuclei.

Administration of 6-hydroxydopamine to neonatal rats results in a permanent increase in the norepinephrine content in several brainstem areas. To assess the physiological effects of this hyperinnervation, we studied the noradrenergic inhibition of transmission of sensory information through the principal sensory and rostral spinal trigeminal nuclei. Unit activity produced by tactile stimulation of the face was recorded extracellularly from trigeminal sensory neurons in normal and hyperinnervated rats. The noradrenergic neurons projecting to the trigeminal sensory nuclei (locus coeruleus and the region of the lateral lemniscus) were stimulated 40 ms prior to delivery of a tactile stimulus to the face, producing complete inhibition. The interstimulus interval was then increased in 100 ms increments until the sensory response returned to control values. Compared with controls, the duration of inhibition was 30% longer in hyperinnervated rats and 25% shorter in rats depleted of catecholamines with reserpine and alpha-methyl-p-tyrosine. While the beta-adrenergic blocker, propranolol, had no effect on the duration of inhibition in normal animals, the mean latency of response to tactile stimulation was decreased from 15.3 to 10.4 ms. Propranolol given to hyperinnervated rats decreased the latency of the response to tactile stimulation from 15.1 to 9.1 ms and decreased the duration of inhibition by 40% compared with untreated hyperinnervated rats, suggesting an alteration in numbers or sensitivity of beta-receptors. Since the drug treatment never eliminated the inhibition due to locus coeruleus stimulation, there is also a non-noradrenergic component. We conclude from these observations that noradrenergic hyperinnervation is not completely counteracted by receptor down regulation.

Projections of the feline globus pallidus.

The organization of globus pallidus (GP) projections was studied in cats using autoradiographic and horseradish peroxidase (HRP) techniques. Both methods confirmed the existence of a topographically organized projection to subthalamic nucleus (STN). Although all but the most caudal GP projects to STN, the heaviest projection is to the lateral two-thirds. In addition, HRP studies showed that the GP projection to the medial part of substantia nigra, pars reticulata receives projections from the rostral lateral GP, while lateral substantia nigra receives input from caudal GP. There is in addition a small projection from caudal GP to the caudal lateral mesencephalon. This most caudal projection of GP arises from the portion of GP which projects the least to the subthalamic nucleus. Mesencephalic and pontine cells labeled after injection of horseradish peroxidase into STN were in areas receiving projections from GP and entopeduncular nucleus, suggesting there may be reciprocal relationships between these areas. Labeled cells were located in the lateral part of subthalamic nucleus after injection into the lateral portion of substantia nigra pars reticulata, but cells were not labeled after medial injection. Pontine injections of HRP also revealed that cells in fields of Forel and zona incerta project to pons but very few subthalamic nucleus cells project there.

Fluoro-Gold's toxicity makes it inferior to True Blue for long-term studies of dorsal root ganglion neurons and motoneurons.

We studied the long-term effects of two retrogradely transported fluorescent dyes on survival of dorsal root ganglion neurons (DRGNs) and motoneurons (MNs). In adult female rats, we labeled DRGNs and MNs by soaking the cut sciatic nerve in Fluoro-Gold or True Blue. With True Blue, we found no difference in the number of labeled MNs or DRGNs in rats surviving 4 days or 20 weeks after nerve soak. With Fluoro-Gold, labeled DRGNs and MNs were decreased at 20 weeks compared with 4 days. Since there was no offsetting increase in unlabeled DRGNs at 20 weeks, Fluoro-Gold caused cell death.

Ventral horn motoneurons 10, 20 and 52 weeks after T-9 spinal cord transection.

To determine if transneuronal degeneration occurs in ventral horn motoneurons caudal to a spinal cord transection, we completely transected the spinal cord at T-9 in seven-week-old female rats. Ten, 20 or 52 weeks later, the motoneurons of the right sciatic nerve of transected and control rats were retrogradely labeled with Fluoro-Gold. There were no differences between control and transected rats in numbers or rostrocaudal distribution of labeled motoneurons at either 10, 20 or 52 weeks. At 20 weeks, there was no significant difference between control and transected rats in mean cross-sectional area of labeled neurons. We conclude that transneuronal degeneration did not occur.

Organization of some brainstem and limbic connections of the hypothalamus.

Electrophysiological and anatomical studies allow the formulation of some features of organization of the lateral hypothalamus: (1) The HVM is the major source of modulatory inpur to the lateral hypothalamus; (2) There is a high degree of convergence of afferent paths in the lateral hypothalamus resulting in the same type of postsynaptic firing pattern, whether it be inhibition or excitation; (3) The response to afferent activation is usually quite simple, consisting of either a brief excitatory period or a fifty to several hundred millisecond inhibition. Complex firing patterns in a response to afferent stimulation are rare; (4) Descending hypothalamic output activates two classes of neurons in the midbrain; (a) an output with a strong synaptic drive acting upon cells which are not spontaneously active and which do not respond to arousing stimuli, and (b) an output with moderate to weak synaptic drive acting upon cells that are spontaneously active and excited by peripheral arousing stimuli.

Stimulus range influences intensity and hedonic ratings of flavour.

Five concentrations of an artificial orange drink were presented for sensory evaluation in three overlapping concentration ranges. Three sensory panels, each of 30 subjects, rated the concentrations for intensity of flavour (intensity scale), relation to ideal flavour intensity (ideal-point scale), and pleasantness (hedonic scale). Except for the two extreme concentrations, neither of which was presented in more than one range, in all three response tasks the mean rating for a given concentration varied with the concentration range in which it was presented. However, the mean ratings showed good correspondence across response tasks (e.g. the concentration perceived as "moderately sweet" on the intensity scale was perceived as "just right" on the ideal-point scale and of maximal pleasantness on the hedonic scale), suggesting a link between the intensity and hedonic dimensions of sensory experience.