A Systematic Review of Clinical Practice Guidelines for Identification and Management of Frailty.

OBJECTIVE: This study aims to appraise and summarize consistent recommendations from clinical practice guidelines (CPGs) for identification and management of frailty to maintain and improve functional independence of elderly population. METHODS: A systematic search of Ovid MEDLINE, Embase, PubMed, PsycINFO, and CINAHL electronic databases using database-specific search terms in two broad areas "guidelines" and "frailty", and a manual search of websites with the key phrase "frailty guideline" was performed. The inclusion criteria included CPGs focusing on identifying and managing frailty in population >65 years old, published in English since January 2010. Three reviewers independently assessed guideline quality using the AGREE II instrument. Data extraction was performed, followed by compilation and comparison of all recommendations to identify the key consistent recommendations. RESULTS: Six CPGs met the inclusion criteria; however, only three CPGs had high methodological quality in accordance with AGREE II appraisal. The average AGREE II scores of all six CPGs were: 84.5%, 68%, 46.5%, 81.5%, 56.3%, and 60.2% for domains 1-6 (scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability, and editorial independence) respectively. A total of 54 recommendations were identified, with 12 key recommendations suggested frequently by the CPGs. CONCLUSION: The AGREE II instrument identified strengths and weaknesses of the CPGs, but failed to assess clinical implications and feasibility of the guidelines. Further research is needed to improve clinical relevance of CPGs in the identification and management of frailty. The feasibility in implementing these guidelines with regards to cost-effectiveness of frailty screening warrants further investigation.

A validated model of GAG deposition, cell distribution, and growth of tissue engineered cartilage cultured in a rotating bioreactor.

In this work a new phenomenological model of growth of cartilage tissue cultured in a rotating bioreactor is developed. It represents an advancement of a previously derived model of deposition of glycosaminoglycan (GAG) in engineered cartilage by (i) introduction of physiological mechanisms of proteoglycan accumulation in the extracellular matrix (ECM) as well as by correlating (ii) local cell densities and (iii) tissue growth to the ECM composition. In particular, previously established predictions and correlations of local oxygen concentrations and GAG synthesis rates are extended to distinguish cell secreted proteoglycan monomers free to diffuse in cell surroundings and outside from the engineered construct, from large aggrecan molecules, which are constrained within the ECM and practically immovable. The model includes kinetics of aggregation, that is, transformation of mobile GAG species into immobile aggregates as well as maintenance of the normal ECM composition after the physiological GAG concentration is reached by incorporation of a product inhibition term. The model also includes mechanisms of the temporal evolution of cell density distributions and tissue growth under in vitro conditions. After a short initial proliferation phase the total cell number in the construct remains constant, but the local cell distribution is leveled out by GAG accumulation and repulsion due to negative molecular charges. Furthermore, strong repulsive forces result in expansion of the local tissue elements observed macroscopically as tissue growth (i.e., construct enlargement). The model is validated by comparison with experimental data of (i) GAG distribution and leakage, (ii) spatial-temporal distributions of cells, and (iii) tissue growth reported in previous works. Validation of the model predictive capability--against a selection of measured data that were not used to construct the model--suggests that the model successfully describes the interplay of several simultaneous processes carried out during in vitro cartilage tissue regeneration and indicates that this approach could also be attractive for application in other tissue engineering systems.

Multiphase modelling of cell behaviour on artificial scaffolds: effects of nutrient depletion and spatially nonuniform porosity.

This paper contains analysis of a recently formulated multiphase model for the growth of biological tissue that comprises motile cells and water inside a rigid scaffold material. The model is extended here to include a term describing cell proliferation which is mediated by the supply of a diffusible nutrient and to include the case where the scaffold porosity varies in space. Numerical solutions of the model equations are presented for different values of the parameters. Comparison is drawn between the different types of growth that arise when using static or dynamic methods for seeding the scaffold with cells. Analytical solutions are presented for the limiting cases in which the coefficient of drag between the cells and the scaffold is very large or zero. In the limit of large time, solutions reveal preferential tissue growth in the vicinity of the scaffold edge due to depletion of nutrient by the cells, consistent with experimental results. However, it is shown that reducing the coefficient of drag between the scaffold and the cells overcomes the effects of nutrient depletion by increasing cell mobility, thereby leading to improved uniformity of the cell distribution within the scaffold.

Neuronal cell death, nerve growth factor and neurotrophic models: 50 years on.

Viktor Hamburger has just died at the age of 100. It is 50 years since he and Rita Levi-Montalcini laid the foundations for the study of naturally occurring cell death and of neurotrophic factors in the nervous system. In a period of less than 10 years, from 1949 to 1958, Hamburger and Levi-Montalcini made the following seminal discoveries: that neuron cell death occurs in dorsal root ganglia, sympathetic ganglia and the cervical column of motoneurons; that the predictions arising from this observation, namely that survival is dependent on the supply of a trophic factor, could be substantiated by studying the effects of a sarcoma on the proliferation of ganglionic processes both in vivo and in vitro; and that the proliferation of these processes could be used as an assay system to isolate the factor. This work provides a short review mostly of the early history of this subject in the context of the Hamburger/Levi-Montalcini paradigm. This acts as an introduction to a consideration of models that have been proposed to account for how the different sources of growth factors provide for the survival of neurons during development. It is suggested that what has been called the 'social-control' model provides the most parsimonious quantitative description of the contribution of trophic factors to neuronal survival, a concept for which we are in debt to Viktor Hamburger and Rita Levi-Montalcini.

Anthelmintic efficacy against cyathostomins in horses in Southern England.

Cyathostomins are considered to be the most important group of helminths to affect equids due to their high prevalence, potential pathogenicity and ability to develop anthelmintic resistance. Their control relies almost exclusively on frequent anthelmintic use. Currently, fenbendazole (FBZ), pyrantel embonate (PYR), ivermectin (IVM) and moxidectin (MOX) are licensed for use in horses in the UK. With no new anthelmintics likely to be licensed in the near future, it is essential that investigations into the efficacy of current anthelmintics in different locations are performed to help inform control programmes. Here, efficacy of FBZ, PYR, IVM and MOX in horse populations in the South of England was investigated. Horses with a strongyle faecal egg count (FEC) of ≥50 eggs per gram (EPG) were enrolled onto a faecal egg count reduction test (FECRT) study. Efficacy was determined by calculating the percentage reduction in FEC between the group mean at Day 0 and 14 days post-treatment. Efficacy was indicated when a group arithmetic faecal egg count reduction (FECR) of ≥90% was recorded for FBZ and PYR, and ≥95% for IVM and MOX. Between March and December 2012, 404 FECRT were performed on 12 yards examining 101, 110, 93 and 100 equids for FBZ, PYR, IVM, and MOX, respectively. FBZ resistance was identified on all yards (mean FECR range 0-65.8%). On 10 of 12 yards, PYR efficacy was >90% (91.0-99.4%) and on two yards, PYR resistance was suspected (86.8-87.2%). IVM (96.4-100%) and MOX (99.9-100%) were >95% efficacious on all yards. As the prevalence of FBZ resistance was 100%, the future use of this anthelmintic for the control of strongyles should be questioned. PYR should be used strategically to reduce reliance on the macrocyclic lactone class products. Over-dispersion of FEC between horses was observed (average k=0.21) with 80% of the strongyle eggs counted measured in 15% of horses tested, strongly supporting the application of targeted helminth control programmes in this host species.

Travelling-wave behaviour in a multiphase model of a population of cells in an artificial scaffold.

This paper analyses travelling-wave behaviour in a recently-formulated multiphase model for the growth of biological tissue that comprises motile cells and water inside a porous scaffold. The model arises in the context of tissue engineering, and its purpose is to study how cells migrate and proliferate inside porous biomaterials. In suitable limits, tissue growth in the model is shown to occur in the form of travelling waves that can propagate either forwards or backwards, depending on the values of the parameters. In the case where the drag force between the scaffold and the cells is non-zero, the growth of the aggregate can be analysed in terms of the propagation of a constant-speed wavefront in a semi-infinite domain. A numerical (shooting) method is described for calculating the wave speed, and detailed results for how the speed varies with respect to the parameters are given. In the case where the drag force is zero, the size of the aggregate is shown either to grow or to shrink exponentially with time. These results may be of importance in determining the experimental factors that control tissue invasiveness in scaffolds thereby allowing greater control over engineered tissue growth.

Calcium mobilization and spontaneous transient outward current characteristics upon agonist activation of P2Y2 receptors in smooth muscle cells.

A quantitative model is provided that links the process of metabotropic receptor activation and sequestration to the generation of inositol 1,4,5-trisphosphate, the subsequent release of calcium from the central sarcoplasmic reticulum, and the consequent release of calcium from subsarcolemma sarcoplasmic reticulum that acts on large-conductance potassium channels to generate spontaneous transient outward currents (STOCs). This model is applied to the case of STOC generation in vascular A7r5 smooth muscle cells that have been transfected with a chimera of the P2Y(2) metabotropic receptor and green fluorescent protein (P2Y(2)-GFP) and exposed to the P2Y(2) receptor agonist uridine 5'-triphosphate. The extent of P2Y(2)-GFP sequestration from the membrane on exposure to uridine 5'-triphosphate, the ensuing changes in cytosolic calcium concentration, as well as the interval between STOCs that are subsequently generated, are used to determine parameter values in the model. With these values, the model gives a good quantitative prediction of the dynamic changes in STOC amplitude observed upon activation of metabotropic P2Y(2) receptors in the vascular smooth muscle cell line.

Metabotropic receptor activation, desensitization and sequestration-I: modelling calcium and inositol 1,4,5-trisphosphate dynamics following receptor activation.

A mathematical account is given of the processes governing the time courses of calcium ions (Ca2+), inositol 1,4,5-trisphosphate (IP(3)) and phosphatidylinositol 4,5-bisphosphate (PIP(2)) in single cells following the application of external agonist to metabotropic receptors. A model is constructed that incorporates the regulation of metabotropic receptor activity, the G-protein cascade and the Ca2+ dynamics in the cytosol. It is subsequently used to reproduce observations on the extent of desensitization and sequestration of the P(2)Y(2) receptor following its activation by uridine triphosphate (UTP). The theory predicts the dependence on agonist concentration of the change in the number of receptors in the membrane as well as the time course of disappearance of receptors from the plasmalemma, upon exposure to agonist. In addition, the extent of activation and desensitization of the receptor, using the calcium transients in cells initiated by exposure to agonist, is also predicted. Model predictions show the significance of membrane PIP(2) depletion and resupply on the time course of IP(3) and Ca2+ levels. Results of the modelling also reveal the importance of receptor recycling and PIP(2) resupply for maintaining Ca2+ and IP(3) levels during sustained application of agonist.

Metabotropic receptor activation, desensitization and sequestration-II: modelling the dynamics of the pleckstrin homology domain.

Recent observations have been made regarding the generation of inositol 1,4,5-trisphosphate (IP(3)), using chimeras of green fluorescent protein and the pleckstrin homology domain of phospholipase C-delta. In this paper a model is presented giving the quantitative relations between the green fluorescent protein-pleckstrin homology domain (GFP-PHD) construct and membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) levels as well as the concentration of IP(3), the product of hydrolysis of PIP(2). The model can correctly reproduce the dependence of cytosolic GFP-PHD fluorescence on IP(3) concentration. This model extends a previous one (Metabotropic receptor activation, desensitization and sequestration-I: modelling calcium and inositol 1,4,5-trisphosphate dynamics following receptor activation, in this issue) dealing with the processes governing the production of IP(3) and the subsequent calcium (Ca2+) changes in cells following activation of metabotropic receptors. This model is applied to the case of purinergic P(2)Y(2) receptor activation in Madin-Darby Canine Kidney (MDCK) cells with adenosine triphosphate (ATP) (Science 284 (1999) 1527). It is shown that it can correctly reproduce the dependence of GFP-PHD fluorescence on the concentration of P(2)Y(2) receptor ligand, as well as the temporal changes of GFP-PHD fluorescence following application of ligand.

Influence of parathyroid state on calcium uptake in bone.

The exchange of calcium and strontium ions in bone was studied in control dogs, dogs made hypocalcemic by parathyroidectomy, and dogs rendered hypercalcemic by injection of parathyroid hormone. After injections of tracer into the tibial nutrient artery, extraction of tracer during transcapillary passage was measured and expressed as a fraction of 1. Extraction over the first 3 min in normal dogs was 0.46 +/- 0.09 (n = 6), in hypocalcemic dogs it was increased to 0.53 +/- 0.07 (n = 6), and in hypercalcemic dogs it was decreased to 0.39 +/- 0.07 (n = 5). Subsequent washout was less rapid than normal in hypoparathyroid dogs and more rapid than normal in hyperparathyroid dogs. We conclude from this that the immediate volume of distribution in bone (or the number of available binding sites) for strontium diminishes as the parathyroid hormone level increases.

Randomized study of adjusted versus fixed low dose heparin prophylaxis of deep vein thrombosis in hip surgery.

A randomized study of adjusted versus fixed low dose heparin prophylaxis has been conducted in 100 patients undergoing surgery for hip replacement or fractured neck of femur. The two types of patients were randomized independently into the adjusted and fixed dose regimens. Patients in the adjusted group were controlled by an activated partial thromboplastin time method particularly responsive to the anticoagulant effect of heparin. The aim was to maintain the peak value just above the upper limit of the normal range. Adjustment of dosage began 24 h after surgery in the replacement group and 24 h after admission in the fracture group. Significant improvement in protection against postoperative deep vein thrombosis, assessed by venography, was observed in the adjusted group undergoing hip replacement (P = 0.013) and overall in both groups (P = 0.017) compared with a conventional fixed dose subcutaneous regimen (calcium heparin 5000 units, 8-hourly). In most instances, adjustment resulted in increased heparin dosage but this was not associated with any evidence of excessive bleeding.

Exchange of potassium and strontium in adult bone.

The kinetics of exchange of strontium (85Sr) and potassium (42K) were studied in the mid-tibial cortical bone of 37 adult dogs. After injection of these two tracer cations and tracer-labeled albumin into the tibial nutrient artery, two types of observations were made: 1) collection of sequential venous samples to provide the outflow indicator-dilution curves and to calculate the extraction and retention at early times; and 2) detection of energy-selected gamma emissions via a detector over the tibia to give the time course of content of 42K and 85Sr in the tibia. Extractions of K+ and Sr2+ were 50 and 60% during a single transcapillary passage. More Sr2+ than K+ was retained in the first minutes. Their rates of washout over a 3-h period were similar. The interpretation is that the rate of uptake at extravascular sites is faster for Sr2+ than for K+, as is the rate of release, and that the extravascular volume of distribution for Sr2+ (adsorption sites in the interstitium or on bone) is much larger than that for K+ (intracellular).

Transcapillary exchange and retention of fluoride, strontium, EDTA, sucrose, and antipyrine in bone.

The extractions of 85Sr2+, 18F-, sucrose-14C, EDTA-51Cr, and antipyrine-14C in bone were determined by the multiple indicator-dilution method. Fluoride and strontium extractions were 18 to 70% during a single transcapillary passage, and those of EDTA and sucrose were from 11 to 59%, whereas extraction of antipyrine was 87%. Injections of 85Sr2+ and 18F- made when perfusion was done alternately with blood and plasma resulted in similar fractional extractions. When flow and extraction were measured simultaneously, extraction was related inversely to flow.

University of Manchester sports injury clinic.

This paper reviews the work of the sports injury clinic based at the Student Health Centre, University of Manchester during its first eighteen months. A total of 852 patients including 46 Centre of Excellence athletes were treated. The results indicate that the establishment of such a specialised clinic is worthwhile, that the injured sportsmen should be treated by individuals trained and interested in the treatment of injured patients in general and that the commonest injuries are soft tissue injuries to the knee of ankle joint. A record card, designed for future computer analysis, is illustrated. It includes details of the sport, training, mechanism of injury, pathology and treatment.