The Scottish national LifeCurve™ survey: costs of functional decline, opportunities to achieve early intervention to support well-being in later life, and meaningfulness of the LifeCurve™.

OBJECTIVES: The aim of the Scottish AHP LifeCurve™ survey was to gather a snapshot of where people are on their LifeCurve™ when receiving allied health professions (AHP) services and to understand the cost consequence of intervening 'late' in the ageing trajectory. The objectives were to promote discussion around preventing functional decline, support innovation in service delivery, and facilitate broader engagement with individuals, communities, and wider environments for improving health and well-being in later life. In addition, subsequent learning could help address the increasing resource gap between the demand and capacity across health and social care. STUDY DESIGN: The survey was paper-based in the form of a printed booklet, which contained the 15 activities of daily living (ADL) and instrumental ADL (IADL) which comprise the LifeCurve™ with additional lifestyle questions and information about the member of staff and service the participant was seen in, including their Community Health Index (CHI) number. The survey questions and booklet layout were tested over a five-month period with AHPs and people receiving AHP services. Liaison with national health literacy colleagues and lead speech and language therapists ensured that the survey material was accessible to a wide range of people. In addition, the survey could be made available in alternative formats, on request. METHODS: Agreement to undertake the national survey was obtained in November 2016 by all AHP directors and associate directors who appointed communication support leads in their area who would support implementation at all stages at a local level. All materials relating to the survey were published on a dedicated area of a community of practice to support awareness and training during the preimplementation phase. AHPs working in adult services were asked to complete a survey with a minimum of two people they would 'typically' see in their service during a two-week period in May 2017, with the exclusion of people who were too unwell to participate, children and young people under 16 years, and adults with incapacity and without a guardianship arrangement in place. Approval was gained from the Public Benefit Privacy Panel to link the survey data to participants' health service usage using their CHI number. Completed forms were returned to the University of Strathclyde for entry into an encrypted electronic database using a double data entry process and were allocated a unique identifier. The unique identifier and CHI numbers were sent to Information Services Division (ISD), and then, the CHI numbers were deleted from the encrypted database. ISD sent the linked health data to the Scottish Government Analytical Services Division, which thus produced a full encrypted and anonymised database. RESULTS: The data explain what stages on the LifeCurve™ AHPs are intervening, and the matched data provide associated healthcare costs at each stage. Due to poor or missing data in the AHP/Service section, only 60% (n = 8261) of the total completed surveys were able to be matched with health service usage records. These data show that whilst AHPs are seeing people at each of the 15 ADL/IADL stages on the LifeCurve™, interventions fell into three groups where 25% of people where seen at the 'precurve' stage, 13% of people at 'mid-curve' (stage number five), and 39% of people at 'late-curve' (stages 10 to 13). The healthcare cost usage of these participants increased the further along the LifeCurve™ a person moves, with an average annual cost of £2700 at 'precurve' rising to £12,330 at 'late-curve' in 2016-2017. The results indicate that different services and professions are represented at each of these three points. So, for example, as might be expected, outpatient (especially musculoskeletal) services were seen more often at the 'precurve' stage, and in-patient and community rehabilitation, services were seen more often at the 'late-curve' stages; diagnostic radiographers and orthoptists saw people at the 'early-curve' stages, dieticians and podiatrists saw people at the 'mid-curve' stage, whilst physiotherapists, speech and language therapists, and occupational therapists saw people at the 'late-curve' stages. Data analysis showed this pattern is different for people receiving mental health services and, so, their data were removed and will be analysed and reported separately. CONCLUSIONS: It is clear from the results that healthcare costs increased as participants moved down LifeCurve™ stages, that is, as their levels of functional decline increase. It is also clear that AHPs are intervening late in a person's functional decline with associated limitations on changing their ageing trajectory. The cost consequence of this is significant - moving someone from 'late- to mid-curve' could save £3200 per person per annum. However, those AHPs typically associated with reabling approaches and rehabilitation, which have greatest potential to change ageing trajectories, were not represented at the 'mid-curve' stage (e.g., physiotherapists, occupational therapists). Therefore, we must find places to have conversations with people to inform them that functional decline is malleable and not inevitable purely by virtue of chronological age and provide education and support to prevent or reverse functional decline and collaborate around strategic planning and commissioning to offer different options that support an optimum LifeCurve™.

Differential conditioning of associative synaptic enhancement in hippocampal brain slices.

An electrophysiological stimulation paradigm similar to one that produces Pavlovian conditioning was applied to synaptic inputs to pyramidal neurons of hippocampal brain slices. Persistent synaptic enhancement was induced in one of two weak synaptic inputs by pairing high-frequency electrical stimulation of the weak input with stimulation of a third, stronger input to the same region. Forward (temporally overlapping) but not backward (temporally separate) pairings caused this enhancement. Thus hippocampal synapses in vitro can undergo the conditional and selective type of associative modification that could provide the substrate for some of the mnemonic functions in which the hippocampus is thought to participate.

Apparent desensitization of NMDA responses in Xenopus oocytes involves calcium-dependent chloride current.

N-Methyl-D-aspartate (NMDA) receptors were expressed and studied in Xenopus oocytes injected with rat brain RNA. NMDA application elicits a rapid inward current that decays in several seconds to a relatively stable level. This decay is reportedly due to desensitization. However, we found the early transient component could be evoked more than once during a single application of NMDA, suggesting that the receptor did not actually desensitize. Removal of external Ca2+, replacement of Ca2+ with Ba2+, or intracellular injection of EGTA abolished the transient component. Furthermore, a variety of Cl- channel blockers nearly eliminated the transient component and inhibited the plateau current as well. We propose that a significant portion of the NMDA current recorded in oocytes is carried by a transient inward Cl- current triggered by Ca2+ influx through the NMDA receptor/channel.

Effects of nitroprusside and redox reagents on NMDA receptors expressed in Xenopus oocytes.

We have examined the effects of oxidizing and reducing agents and sodium nitroprusside (SNP) on currents evoked by NMDA (N-methyl-D-aspartate) using the Xenopus oocyte expression system. Oocytes were injected with RNA prepared from either whole rat brain or from the NMDAR1 clone recently isolated from rat brain. Bath application of 1-1000 microM SNP, which releases nitric oxide and ferrocyanide, caused a rapid inhibition of NMDA-evoked current in both preparations. The inhibitory effect reversed spontaneously within 15 min. Kainate responses were not affected by SNP. Exposure to the reducing agent, dithiothreitol (DTT), enhanced NMDA currents; the oxidant, 5,5-dithio-bis-2-nitrobenzoic acid (DTNB), inhibited NMDA responses, as has been observed in other preparations. The site of action of SNP appeared to be different than the DTT/DTNB redox site for several reasons: SNP and DTNB inhibitions were additive at high doses, DTT did not rapidly reverse SNP effects, and SNP and DTT treatments did not show the same susceptibility to block by the NMDA antagonist, aminophosphonovaleric acid (APV). The results demonstrate that modulation of NMDA receptors by SNP is a property of homomeric channels and is retained when the NMDAR1 subunit is expressed in oocytes.

Activity-induced depression of synaptic inhibition during LTP-inducing patterned stimulation.

In the hippocampus, patterns of electrical stimulation that approximate bursting neuronal activity during theta rhythm have been shown to induce a long-term potentiation (LTP) of excitatory synapses. In this study, a single subthreshold stimulus applied to one set of Schaffer/commissural fibers affected the response to a second stimulation delivered 200 ms later to a separate set of Schaffer/commissural fibers in the CA1 field of rat hippocampal slices. The first (priming) stimulus caused a prolongation of the synaptic response elicited by the second (primed) stimulus. In addition, the priming stimulation facilitated the induction of LTP by bursts of stimulation (4 pulses at 100 Hz) of the second afferent pathway. Analysis of the shape of the synaptic responses indicates that the prolongation is due to the removal of an inhibitory component rather than the addition of a novel excitatory component. Blockade of GABAA-ergic transmission with picrotoxin mimicked the priming effect in that it also widened synaptic responses and facilitated burst-induced LTP. We suggest that these patterns of stimulation result in a transient loss of inhibition during the primed stimulation. This, in turn, brings about a prolongation of the synaptic response that allows short bursts of excitatory synaptic activity to depolarize postsynaptic cells sufficiently to trigger LTP.

Trans-ACPD reduces multiple components of synaptic transmission in the rat hippocampus.

Activation of metabotropic quisqualate receptors by trans-ACPD (trans-1-aminocyclopentane-1,3-dicarboxylic acid) caused a reduction in the amplitude of the synaptic response elicited by stimulation of the Schaffer collateral projection and recorded intracellularly from area CA1 in slices of rat hippocampus. Pharmacological agents were used to isolate components of the response mediated by N-methyl-D-aspartate (NMDA) receptors, non-NMDA receptors, and gamma-aminobutyric acid (GABA) receptors. Each of these components was reduced during the trans-ACPD application. These results indicate that one subtype of glutamate receptor may be able to decrease the synaptic efficacy of other subtypes and may provide an important means for balancing the synaptic enhancement processes often studied in the hippocampus.

Oxygen consumption of hypothalamic tissue slices after varying incubation periods.

In order to quantitate possible time-related changes in the viability of rat hypothalamic tissue slices, tissue oxygen consumption was measured after incubation periods ranging from 0-4 hours. There were no significant differences in mean tissue oxygen consumption between the various incubation periods; nor was there any trend indicating that oxygen consumption gradually decreases over time. Moreover, no regional differences were observed among the various rostral hypothalamic slices. One obvious trend, however, was that during the first two hours of each experiment, tissue oxygen consumption decreased briefly and then returned to normal higher levels. The exact occurrence of this transitory decrease varied from experiment to experiment; but the subsequent recovery in oxygen consumption was always complete by two hours of incubation. This initial transient decrease in tissue oxygen consumption may reflect the initial period of electrophysiological inactivity reported in several in vitro studies.

A slice chamber for intracellular and extracellular recording during continuous perfusion.

The design of a tissue slice perfusion system is described, and examples are given showing the stability of this system for intracellular and extracellular recordings during changes in perfusion media. The stability of this system is attributed to several features. Mini-drips serve to cushion transient changes in flow rate when switching from one medium to another. Solenoid valves are used to quickly switch perfusion media with minimal mechanical movement. A finely-controlled adjustable flow valve provides a uniform flow rate for all media. Constant tissue temperature is maintained by media perfusion through a thermoelectric Peltier assembly. In addition, a filter paper wick insures that the perfusate is constantly removed without movement in the tissue slices. With this design, the slices are supported on a net at the interface between the perfusion medium and a humidified, oxygenated atmosphere. This arrangement appears to be conducive to tissue viability and facilitates the placement of microelectrodes in the slices.

Aerobic Dance Injuries: A Retrospective Study of Instructors and Participants.

In brief: In this study shoes, floor types, and individual physical differences were evaluated for their effects on aerobic dance injuries. The injury frequency was 75.9% for instructors and 43.3% for students. The shin was the most common site of injury in both groups. Overall, 60% of the injuries in the student group and 52% of injuries in the instructor group occurred below the knee. Most injuries were not debilitating, and few required medical treatment. The authors concluded that resilient but stable floor surfaces, proper shoes, and moderating the frequency of participation can prevent injuries in aerobic dance.

Evaluation of mechanical tractor pedal extensions.

Many farmers with disabilities choose to modify their work environments to accommodate their personal abilities; however, modified tractors may present greater risk to the operator as they are often one-of-a-kind designs that have not been subjected to rigorous safety testing. The objective of this research was to evaluate mechanical tractor pedal , extensions from a safety perspective. This objective was achieved by identifying potential hazards associated with the introduction of a pedal extension into the cab environment so that both existing and novel designs could be compared using a common methodology. Based on review of the published literature, 19 potential hazards associated with the introduction of a pedal extension into the cab of a tractor were identified. A hazard self-assessment worksheet (HSAW), created based on the 19 hazards, was validated through a pilot study. The overall inter-rater reliability and concurrent criterion validity proved to be acceptable. With the use of the HSAW six pedal extensions (three existing designs and three novel designs) were evaluated by 14 experts. Statistical analysis of the results did not identify a "best" design; however, several important trends were observed. Four of the six designs tended to block access to the exit path. The two designs that did not block access to the exit path might be considered to be the best designs for the tractors used in this study, but other designs likely would have been acceptable if they had been custom-fit for these tractors. The results of this research suggest that custom fabrication of pedal extensions for each specific tractor will likely yield the safest work environment for those who choose to use this assistive technology.

Effect of synaptic blockade on thermosensitive neurons in hypothalamic tissue slices.

To understand the basis of hypothalamic neuronal thermosensitivity, single-unit activity was recorded in vitro, from constantly perfused tissue slices of rat preoptic area and anterior hypothalamus, PO/AH. The firing rate and thermosensitivity of individual PO/AH neurons was determined before, during, and after tissue perfusion with a synaptic blocking medium, containing elevated magnesium and decreased calcium concentrations. During synaptic blockade, thermosensitivity was retained in nearly all of the warm-sensitive neurons, and some temperature-insensitive neurons showed increased warm sensitivity. The thermosensitivity of all cold-sensitive neurons was lost during synaptic blockade. These results support the hypothesis that PO/AH cold-sensitive neurons depend on synapses from nearby warm-sensitive neurons for their temperature sensitivity; whereas warm sensitivity is an independent property of certain PO/AH neurons.

Activity-induced decrease in early and late inhibitory synaptic conductances in hippocampus.

The use dependence of inhibitory postsynaptic potentials (IPSPs) and their underlying conductances was studied in area CA1 of the hippocampal brain slice preparation, using a two-pulse paradigm in which paired activation of two separate synaptic inputs resulted in changes in the second, or "primed" response. In intracellular current-clamp recordings, the "primed" response, normally triphasic, exhibited a larger, wider excitatory PSP (EPSP) component and greatly reduced or absent IPSP components. Maximal widening occurred when the interval between synaptic stimuli was between 200 and 250 msec. Hyperpolarization of the postsynaptic cell reversed both the early IPSP and the direction of change of the width of the "primed" EPSP response, suggesting that the changes in the "primed" waveform were not due to the addition of an unidentified inward current(s). Furthermore, the reduction of the IPSPs during the "primed" response could not be accounted for by the fact that the membrane potential of the postsynaptic cell was hyperpolarized and therefore closer to IPSP reversal potential. Using single-electrode voltage-clamp techniques, we found that the early inhibitory conductance generally decreased by approximately 50%, with little if any change in reversal potential. The late inhibitory conductance also showed a priming-induced decrease of approximately 95%. Finally, "primed" four-pulse bursts of stimuli induced a larger depolarization in the postsynaptic cell than did unprimed bursts, also with an optimal interval of about 250 msec. We conclude that activation of certain synaptic pathways in the hippocampus results in a temporal window of 200-300 msec during which inhibitory synaptic activity is depressed and excitatory synaptic transmission is maximally effective, especially if the excitation occurs in short bursts. Such a mechanism would endow the inhibitory synaptic components of the hippocampus with a "gating" function to control long-term synaptic modification at excitatory synapses in the same region.

Intracellular analysis of inherent and synaptic activity in hypothalamic thermosensitive neurones in the rat.

1. Intracellular neuronal activity was recorded in rat preoptic-anterior hypothalamic tissue slices. Thirty neurones were classified as warm sensitive, cold sensitive or temperature insensitive, based on their firing rate response to temperature changes. Seventy-seven per cent of the neurones were temperature insensitive, which included both spontaneously firing and silent neurones. Of all neurones, 10% were warm sensitive and 13% were cold sensitive. 2. Silent temperature-insensitive neurones had lower input resistances (126 +/- 21 M omega) than thermosensitive neurones (179 +/- 24 M omega). Regardless of neuronal type, however, resistance was inversely related to temperature. 3. Warm-sensitive neurones were characterized by a slow, depolarizing pre-potential, whose rate of rise was temperature dependent. This depolarizing potential disappeared during current-induced hyperpolarization, suggesting that intrinsic mechanisms are responsible for neuronal warm sensitivity. 4. Spike activity in cold-sensitive neurones correlated with putative excitatory and inhibitory postsynaptic potentials, whose frequency was thermosensitive. This suggests that cold sensitivity in these neurones depends on synaptic input from nearby neurones. 5. Like cold-sensitive neurones, action potentials of temperature-insensitive neurones often were preceded by short duration (less than 20 ms), rapidly rising pre-potentials, whose rates of rise were not affected by temperature. In some temperature-insensitive neurones, depolarizing current injection increased both firing rate (by 5-8 impulses s-1) and warm sensitivity, with pre-potentials having temperature-dependent rates of rise. We suggest that temperature-insensitive neurones employ two opposing, thermally dependent mechanisms: a voltage-dependent depolarizing conductance and a hyperpolarizing sodium-potassium pump.

Hebbian synapses in hippocampus.

A combination of current- and voltage-clamp techniques applied to hippocampal brain slices was used to evaluate the role of postsynaptic electrogenesis in the induction of associative synaptic enhancement. In accordance with Hebb's postulate for learning, repetitive postsynaptic spiking enabled enhancement in just those synapses that were eligible to change by virtue of concurrent presynaptic activity. However, the essential postsynaptic electrogenic event that controlled the enhancement was shown to involve biophysical processes that were unknown when Hebb formulated his neurophysiological postulate. The demonstrated spatiotemporal specificity of this pseudo-Hebbian conjunctive mechanism can account qualitatively for the known neurophysiological properties of associative long-term potentiation in these synapses, which in turn can explain the "cooperativity" requirement for long-term potentiation.

Protein kinase C-mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes.

1. N-Methyl-D-aspartate (NMDA) receptors were expressed in Xenopus oocytes injected with rat brain RNA. The modulation of NMDA-induced currents was examined by activating protein kinase C (PKC) either directly (using phorbol esters) or indirectly (via metabotropic glutamate agonists). 2. Bath application of the PKC activator, 4-beta-phorbol-12,13-dibutyrate (PDBu) resulted in a two-fold increase in the NMDA-evoked current at all holding potentials examined (-80 to 0 mV). The inactive (alpha) stereoisomer of phorbol ester was ineffective. 3. The increase was observed under conditions that eliminate the oocyte's endogenous calcium-dependent chloride current, which often contributes to the NMDA response in oocytes. 4. The PDBu effect was specific to the NMDA subclass of glutamate receptors in that no increase was observed in the responses to two other glutamate agonists, kainate and AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid). 5. Stimulation of PKC by activation of metabotropic receptors via either quisqualate or trans-ACPD (trans-1-aminocyclopentane-1,3-dicarboxylic acid) also led to an increase in NMDA currents. 6. Both methods of enhancement induced transient effects. PDBu effects lasted 10-45 min, depending upon both dose and length of application. Quisqualate and trans-ACPD effects were shorter, lasting less than 10 min under these conditions of application. 7. Both methods of enhancement were blocked by the PKC inhibitor, staurosporine. In addition, the phorbol ester-induced enhancement of NMDA responses occluded further enhancement by quisqualate. 8. The results suggest a role for metabotropic glutamate receptors in modulation of NMDA-mediated processes.

Thermosensitive single-unit activity of in vitro hypothalamic slices.

Single-unit activity was recorded in vitro from tissue slices of rat preoptic area-anterior hypothalamus. The thermosensitivity of 139 units was determined by their changes in firing rate in response to changes in slice temperature. Of these neurons, 30% were warm sensitive, 10% were cold sensitive, and 60% were temperature insensitive. These proportions are similar to results obtained in whole-animal studies, indicating that this is a viable preparation. It also suggests that hypothalamic neuronal thermosensitivity is not dependent on peripheral afferent input. All units had low firing rates (less than 10 imp/s) at 37 degrees C, and 83% of the warm-sensitive units were most thermosensitive above 37 degrees C. This supports the concept that afferent input determines the level of firing rate and range of thermosensitivity of warm-sensitive neurons. The cold-sensitive units also displayed maximal thermosensitivity above 37 degrees C, which would be expected if cold-sensitive neurons received inhibitory synaptic input from nearby warm-sensitive neurons.

Conductance mechanism responsible for long-term potentiation in monosynaptic and isolated excitatory synaptic inputs to hippocampus.

The biophysical mechanisms underlying long-term potentiation (LTP) were investigated in identifiable and monosynaptic excitatory inputs to hippocampal neurons. The results provide the first insights into the conductance changes that are responsible for the expression of LTP. Both current- and voltage-clamp measurements of the mossy fiber synaptic response in pyramidal neurons of region CA3 were made with a single-electrode-clamp system. The excitatory postsynaptic response was pharmacologically isolated by bathing hippocampal slices in saline containing 10 microM picrotoxin, which blocks the synaptic inhibition that normally accompanies the experimentally evoked mossy fiber response. LTP was induced by tetanically stimulating the mossy fiber input for 1 s at 100 Hz. Before and 20 min to 1 h after inducing LTP, we attempted to measure the mean excitatory postsynaptic potential (EPSP) amplitude, intrasomatic current-voltage relationship to a step (RN) or alpha function (AN) current waveform, membrane time constant (tau m), spike threshold (T50), peak excitatory postsynaptic current amplitude (IP), synaptic conductance increase (delta G), and synaptic reversal potential (VR); but adequate assessments of all eight of these were not always obtained for every cell that was studied. The induction of LTP increased the mean (+/- SE) EPSP amplitude form 10.5 +/- 1.4 mV during the control period to 16.8 +/- 2.4 mV after the induction of LTP (n = 14; P less than 0.05). This change was not accompanied by increases in the mean value of RN (63 +/- 11 M omega before and 61 +/- 11 M omega after induction; n = 8; P greater than 0.05); AN, which approximates the effective synaptic input resistance at the soma (10.0 +/- 1.50 M omega before and 10.5 +/- 1.60 M omega after; n = 10; P greater than 0.05); or tau m (22 +/- 2 ms before and 20 +/- 2 ms after; n = 8; P greater than 0.05). There was no significant change in T50, which was also assessed with an alpha function current waveform (1.48 +/- 0.11 nA before and 1.49 +/- 0.10 nA after; n = 6; P greater than 0.05). The mean value of IP increased from 1.1 +/- 0.2 nA during the control period to 1.8 +/- 0.3 nA after inducing LTP (n = 15; P less than 0.05). Similarly, delta G increased from 30 +/- 4 nS before to 47 +/- 4 nS after induction (n = 10; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Subunit-specific redox modulation of NMDA receptors expressed in Xenopus oocytes.

We have examined the effects of oxidizing and reducing agents on a number of subtypes of N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus oocytes. Oocytes were injected with cRNA for the zeta 1 subunit from mouse to express homomeric receptors or with zeta 1 in combination with either epsilon 1, epsilon 2, epsilon 3 or epsilon 4 subunits to express heteromeric receptors. All heteromeric combinations resulted in receptors that were affected by the redox reagents, dithiothreitol (DTT) and 5-5-dithio-bis-2-nitrobenzoic acid (DTNB). However, the effects on the small currents from homomeric receptors were quite variable. The zeta 1/epsilon 3 combination showed a greater enhancement by DTT than any of the other combinations. All four receptors expressed showed both a component of persistent potentiation and a slowly reversible component. The reversible component was largest for zeta 1/epsilon 3. Additional experiments were done with S-nitrosocysteine (SNOC), a nitric oxide donor that may affect NMDA receptors by oxidation. SNOC had transient effects on the four heteromeric subunit combinations. The different sensitivities of particular subunit combinations may have pharmacological and clinical significance.

Intracellular injections of EGTA block induction of hippocampal long-term potentiation.

Hippocampal long-term potentiation (LTP) is a remarkably stable facilitation of synaptic responses resulting from very brief trains of high-frequency stimulation. Because of its persistence and modest induction conditions, LTP represents a promising candidate for a substrate of memory. Some progress has been made in localizing the changes responsible for the effect; for example, it has been shown that LTP is not accompanied by changes in the fibre volleys of the test afferents or by generalized alterations of the dendrites of their target cells. However, it is unknown whether the potentiation is due to pre- or postsynaptic changes and there is evidence in favour of each (for example, see refs 5, 6). We now report that intracellular injections of the calcium chelator EGTA block the development of LTP. These results strongly suggest that LTP is caused by a modification of the postsynaptic neurone and that its induction depends on the level of free calcium.