Using family and staff experiences of a botulinum toxin-A service to improve service quality.

BACKGROUND: The decision for families to proceed with botulinum toxin-A (BoNT-A) injections for managing childhood conditions involving hypertonia can be complex. Family-centred care is a service model that facilitates supporting families in this decision-making process. Understanding families' experiences of services is critical to developing family-centred care. The aim of this project was therefore to increase understanding of the experiences of families of children attending a BoNT-A service in order to improve the service and its family-centred approach to care. METHOD: Sixteen staff of a BoNT-A service participated in a patient journey mapping exercise. Nine families of the service participated in in-depth interviews. Interviews were audio-recorded and transcribed verbatim. Data from the staff session and interviews were analysed independently using grounded, hermeneutic thematic analysis. RESULTS: Staff sessions revealed 5 core themes that related to impacting on the family experience. Family interviews revealed 4 core themes, with 7 subthemes and 1 latent theme. CONCLUSIONS: Areas of importance identified by families relating to BoNT-A treatment included acknowledgement of individual needs, care coordination, empowerment of families and patients, consistency in service delivery, and the distressing nature of appointment and decision-making. Comparison of the data from the staff patient journey mapping and family interviews suggested that staff have a good but incomplete understanding of the factors important to families, highlighting the need for consumer engagement in establishing family-centred care. The themes identified can guide the provision of family-centred BoNT-A injection clinics.

Conformal rotation therapy with central axis beam block is a feasible alternative to intensity-modulated radiotherapy for chordomas of the cervical spine.

AIMS: Paraspinal tumours, such as chordoma, represent a treatment challenge for oncologists, requiring high dose to the target volume without exceeding the tolerance dose of the spinal cord. Intensity-modulated radiotherapy (IMRT) is helpful in achieving sharp dose gradients and conformation of dose to the target volume. We present a simpler technique--conformal rotation therapy with a central axis beam block (CRT + BB), which can provide similar dose distributions. MATERIALS AND METHODS: A patient with a cervical chordoma developed postoperative recurrence and was treated with high-dose palliative radiotherapy. Treatment was delivered using CRT + BB, with three fixed beams and three coplanar arcs. A dose of 62 Gy in 31 fractions was delivered to the 100% isodose, giving a maximum spinal cord dose of 49.6 Gy. The patient relapsed 2 years later, and was re-treated using the same technique to a dose of 57 Gy in 30 fractions. Estimates of spinal cord repair rates in primates were used to determine the tolerance dose of the spinal cord for re-treatment. The patient remained well for a further 25 months before developing local recurrence, which was treated with palliative chemotherapy. RESULTS: Re-treatment plans using CRT + BB and IMRT were compared. Dose-volume histograms show equivalence of dose to the spinal cord, although the IMRT plan delivered a slightly higher dose to tumour and lower dose to surrounding soft tissues. CONCLUSION: Treatment using CRT + BB requires careful planning and discussion with neurosurgeons before surgery. The normal curvature of the cervical spine must be eliminated if possible, and the patient must be immobilised with the neck horizontal. If these geometric constraints can be satisfied, then CRT + BB can be used as a safe and effective alternative treatment to IMRT for tumours at this site.

UK Back pain Exercise And Manipulation (UK BEAM) trial--national randomised trial of physical treatments for back pain in primary care: objectives, design and interventions [ISRCTN32683578].

BACKGROUND: Low back pain has major health and social implications. Although there have been many randomised controlled trials of manipulation and exercise for the management of low back pain, the role of these two treatments in its routine management remains unclear. A previous trial comparing private chiropractic treatment with National Health Service (NHS) outpatient treatment, which found a benefit from chiropractic treatment, has been criticised because it did not take treatment location into account. There are data to suggest that general exercise programmes may have beneficial effects on low back pain. The UK Medical Research Council (MRC) has funded this major trial of physical treatments for back pain, based in primary care. It aims to establish if, when added to best care in general practice, a defined package of spinal manipulation and a defined programme of exercise classes (Back to Fitness) improve participant-assessed outcomes. Additionally the trial compares outcomes between participants receiving the spinal manipulation in NHS premises and in private premises. DESIGN: Randomised controlled trial using a 3 x 2 factorial design. METHODS: We sought to randomise 1350 participants with simple low back pain of at least one month's duration. These came from 14 locations across the UK, each with a cluster of 10-15 general practices that were members of the MRC General Practice Research Framework (GPRF). All practices were trained in the active management of low back pain. Participants were randomised to this form of general practice care only, or this general practice care plus manipulation, or this general practice care plus exercise, or this general practice care plus manipulation followed by exercise. Those randomised to manipulation were further randomised to receive treatment in either NHS or private premises. Follow up was by postal questionnaire one, three and 12 months after randomisation. The primary analysis will consider the main treatment effects before interactions between the two treatment packages. Economic analysis will estimate the cost per unit of health utility gained by adding either or both of the treatment packages to general practice care.

Nutrition-hormone receptor-gene interactions: implications for development and disease.

Nutrition profoundly alters the phenotypic expression of a given genotype, particularly during fetal and postnatal development. Many hormones act as nutritional signals and their receptors play a key role in mediating the effects of nutrition on numerous genes involved in differentiation, growth and metabolism. Polypeptide hormones act on membrane-bound receptors to trigger gene transcription via complex intracellular signalling pathways. By contrast, nuclear receptors for lipid-soluble molecules such as glucocorticoids (GC) and thyroid hormones (TH) directly regulate transcription via DNA binding and chromatin remodelling. Nuclear hormone receptors are members of a large superfamily of transcriptional regulators with the ability to activate or repress many genes involved in development and disease. Nutrition influences not only hormone synthesis and metabolism but also hormone receptors, and regulation is mediated either by specific nutrients or by energy status. Recent studies on the role of early environment on development have implicated GC and their receptors in the programming of adult disease. Intrauterine growth restriction and postnatal undernutrition also induce striking differences in TH-receptor isoforms in functionally-distinct muscles, with critical implications for gene transcription of myosin isoforms. glucose transporters, uncoupling proteins and cation pumps. Such findings highlight a mechanism by which nutritional status can influence normal development, and modify nutrient utilization. thermogenesis. peripheral sensitivity to insulin and optimal cardiac function. Diet and stage of development will also influence the transcriptional activity of drugs acting as ligands for nuclear receptors. Potential interactions between nuclear receptors, including those for retinoic acid and vitamin D, should not be overlooked in intervention programmes using I or vitamin A supplementation of young and adult human populations

Effects of different oxidative insults on intermediary metabolism in isolated perfused rat hearts.

13C and 31P NMR were used to evaluate exogenous substrate utilization and endogenous phosphate metabolites in perfused rat hearts exposed to tert-butylhydroperoxide (tert-BOOH) and hydrogen peroxide (H2O2). Both reagents caused a reduction in developed pressure compared to controls and, in agreement with previous 31P NMR data, had different effects on intracellular high-energy phosphates and glycolysis. 13C Isotopomer analysis of tissue extracts showed that H2O2 and tert-BOOH also had significantly different effects on substrate utilization by the citric acid cycle. The contribution of exogenous lactate and glucose to acetyl-CoA was 43% in controls and increased to over 80% in the presence of either oxidant. With tert-BOOH, exogenous glucose and lactate were both significant contributors to acetyl-CoA (44 +/- 2 and 41 +/- 3%). However, with H2O2, exogenous lactate supplied a much higher fraction of acetyl-CoA (72 +/- 2%) than glucose (9 +/- 1%). Also, when [2-(13)C] glucose was supplied, accumulation of [2-(13)C] and [5-(13)C] fructose 1,6-bisphosphate was observed in the presence of H2O2, indicating inhibition of glyceraldehyde-3-phosphate dehydrogenase. These results indicate that despite this glycolytic inhibition, H2O2 increased the utilization of pyruvate precursors when lactate was present as an alternative carbohydrate substrate.

Effects of oxidant exposure on substrate utilization and high-energy phosphates in isolated rat hearts.

The effects of a xanthine oxidase-mediated free radical-generating system containing purine and iron-loaded transferrin or solutions containing hydrogen peroxide and iron-loaded transferrin on substrate utilization and high-energy phosphates were evaluated by nuclear magnetic resonance (NMR) spectroscopy in isolated perfused rat hearts. Hearts were supplied with lactate, acetate, and glucose, and the contribution of each substrate to acetyl coenzyme A was measured in control hearts and in the presence of a free radical-generating system. Perfused hearts were monitored by 31P NMR, and tissue extracts were analyzed by 13C NMR. Free radicals decreased the phosphocreatine and beta-ATP peak areas and reduced contractile function. Under control conditions, lactate, acetate, and endogenous sources were the major contributors of acetyl coenzyme A units, with only 5% originating from glucose. In the presence of a xanthine oxidase-mediated free radical-generating system, the glucose contribution increased to 54%, while contributions from acetate and endogenous sources were significantly reduced. Both 13C and 31P NMR analyses showed no significant accumulation of glycolytic sugar phosphates, suggesting little inhibition of glyceraldehyde-3-phosphate dehydrogenase. The increased contribution of glucose to the tricarboxylic acid cycle relative to acetate and endogenous sources is consistent with activation of pyruvate dehydrogenase. In contrast, hearts exposed to a hydrogen peroxide-based free radical-generating system showed an increase in lactate utilization, a decrease in acetate utilization, and no change in glucose utilization compared with control hearts. Glycolytic sugar phosphates were found to accumulate, suggesting possible inhibition of glyceraldehyde-3-phosphate. Thus, different radicals or their metabolites may have varying effects on myocardial metabolism.

Expression and sexual dimorphism of galanin messenger ribonucleic acid in growth hormone-releasing hormone neurons of the rat during development.

In the rat, the secretion of GH is episodic and sexually dimorphic. The development and regulation of this patterning of GH secretion are governed by the reciprocal influence of the hypothalamic peptide somatostatin and GH-releasing hormone (GHRH). Galanin is a neuropeptide that is colocalized with GHRH in hypothalamic neurons and is thought to be involved in generating the episodic pattern of GH secretion. We hypothesized that galanin mRNA expression in GHRH neurons increases over development in both sexes, and that in the adults, galanin expression in GHRH neurons is greater in males than in females. To test these hypotheses, we used a double label in situ hybridization procedure to detect and measure galanin mRNA expression in GHRH neurons in the rat brain. GHRH mRNA-positive cells were visualized by an alkaline phosphatase color reaction, and galanin mRNA levels were measured by counting autoradiographic grains over individual GHRH mRNA-positive cells. Galanin mRNA coexpression was found in GHRH mRNA-containing cells of the arcuate nucleus, periarcuate area, and ventromedial hypothalamus. In both males and females there was a significant increase in galanin mRNA in GHRH neurons over development. Galanin mRNA levels in GHRH neurons of 10- and 25-day-old rats were higher in females than in males [10-day-old: females, 12 +/- 2; males, 6 +/- 1 grains/cell (P < 0.05); 25-day-old: females, 28 +/- 4; males, 15 +/- 3 grains/cell (P < 0.02)]. In adults (70 days), galanin mRNA levels in GHRH neurons were significantly higher in males than in females (males, 54 +/- 4; females, 32 +/- 3 grains/cell; P < 0.005). In the adult rat, galanin mRNA levels in the individual hypothalamic areas exhibited a significant sexual dimorphism in the arcuate nucleus and periarcuate area, with higher levels in the male, whereas no sexual dimorphism was observed in the ventromedial hypothalamus. To determine whether galanin gene expression is influenced by circulating levels of testosterone, we measured galanin mRNA levels in castrated male rats with and without testosterone replacement. Castration reduced galanin message levels in GHRH neurons (intact, 73 +/- 6; castrate, 57 +/- 4 grains/cell), and although this reduction was not statistically significant (P = approximately 0.07), testosterone replacement significantly increased galanin message content (castrate/sham, 58 +/- 4 grains/cell; castrate plus testosterone replacement, 77 +/- 5 grains/cell; P < 0.02) to intact levels (intact, 73 +/- 6 grains/cell). In summary, galanin message expression in GHRH neurons of both male and female rats increases over development.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth hormone receptor messenger ribonucleic acid distribution in the adult male rat brain and its colocalization in hypothalamic somatostatin neurons.

The activity of both somatostatin (SS) and GH-releasing hormone (GHRH) neurons within several hypothalamic nuclei is regulated, in part, by the feedback effects of GH. However, whether GH, or its intermediate, insulin-like growth factor I, acts on these neurons to alter the synthesis and release of SS and GHRH is unknown. We argued that if GH itself acts directly on the brain to govern its own secretion, then regions of the brain containing SS and GHRH neurons may express the GH receptor gene. We tested this hypothesis by performing in situ hybridization for GH receptor messenger RNA (mRNA) and mapping its distribution in the brain. We observed GH receptor mRNA-containing cells in various brain regions including the thalamus, septal region, hippocampus, dentate gyrus, amygdala, and hypothalamus. Next we sought evidence for expression of the GH receptor mRNA by SS neurons in the hypothalamus. We addressed this by performing a double-label in situ hybridization to identify neurons expressing both SS mRNA and GH receptor mRNA. We report that SS neurons in the periventricular nucleus and in the paraventricular nucleus coexpress the GH receptor gene, whereas few, if any, of the SS neurons in the cortex express detectable amounts of the GH receptor mRNA. These findings suggest that GH acts directly on the brain and participates in the regulation of its own secretion through a direct action on hypothalamic SS neurons.

Convulsive status epilepsy: is there a role for thiopentone-induced narcosis?

Convulsive status epilepsy is a medical emergency with significant mortality and morbidity. This retrospective survey reports the use of non-anaesthetic doses of thiopentone, given either by intravenous or rectal infusion. The regime was effective in controlling convulsive status without significant complications. It is suggested that this regime can be used safely when standard doses of diazepam (or clonazepam), and/or phenytoin, fail to effect immediate control of convulsive status, and before anaesthetic agents are administered.

Quantitative x-ray microanalysis of the elemental composition of individual myocytes in hypoxic rabbit myocardium.

The purpose of this study was to use energy dispersive x-ray microanalysis to test the following hypotheses: (1) that individual myocytes may exhibit important variation in the severity of alterations in intracellular ionic homeostasis in response to hypoxia and (2) that hypoxic myocytes may accumulate certain elements in quantities sufficient to impair organellar function and structure. A rabbit interventricular septal preparation with attached small right ventricular papillary muscles was used to obtain control oxygenated myocardium (six papillary muscles) and myocardium rendered hypoxic for 1 to 1 1/2 hr (n = 8). Myocardium not perfused in vitro was also obtained (n = 4). Microanalysis was performed on freeze-dried thin sections of unfixed papillary muscles. Elemental concentrations were determined by suitable cryostandards of elements of interest. Sarcoplasm and mitochondria of most hypoxic myocytes exhibited significant alterations of diffusible elements, including increases in sodium and chloride and decreases in potassium, phosphorus, and magnesium, without major change in calcium. The most severely altered myocytes showed evidence of calcium overloading manifested by markedly increased levels of mitochondrial calcium and phosphorus associated with formation of electron-dense mitochondrial inclusions. Levels of mitochondrial calcium and phosphorus exceeded those previously found to markedly impair the function and structure of isolated mitochondria. Thus x-ray microanalysis of unfixed cryosections provides direct measurements of subcellular alterations in elemental composition of individual myocytes in injured myocardium and demonstrates that both calcium and phosphorus accumulate in mitochondria of severely injured myocytes in concentrations sufficient to exert deleterious effects on these organelles.

Dietary ascorbic acid and resistance to experimental renal candidiasis.

Guinea pigs were maintained for various periods of time on low (0.5 mg/day), intermediate (20 mg/day), or high (100 and 500 mg/day) levels of dietary ascorbic acid. Animals in each experimental group were challenged with Candida albicans via cardiac injection, and the course of infection in the kidneys was assessed. The results show that the animals receiving only 0.5 mg of ascorbic acid per day were significantly more susceptible to the infection than animals maintained on any higher level of dietary ascorbic acid. The greater susceptibility of the guinea pigs in the 0.5-mg level group was evident, however, only during "early" stages of the infection (until about day 3). Guinea pigs receiving high levels of dietary ascorbic acid were no more resistant at any time after infection, or with any challenge dose, than those receiving an intermediate dietary level. Although these data suggest that vitamin C may be involved in resistance to candidiasis, tissue levels of ascorbic acid do not change significantly with time after infection. These results indicate that low levels of dietary ascorbic acid increase susceptibility to candidiasis, yet high (or "megadose") levels of dietary vitamin C do not show any effect on resistance to this microorganism.

Endocytosis and immunoglobulin transport across the small intestine of the new-born pig.

1. Measurements of porcine and human IgG transport across the small intestine of the new-born pig have been made in vivo and related to the amount of endocytosis taking place.2. The amount of immunoglobulins transported, following intraduodenal administration to conscious animals, is directly related to the degree of endocytosis which these proteins produce. Administration of protein in amounts sufficient to cause a maximal endocytotic response causes saturation of the protein transporting process.3. Absorption of small amounts of human IgG from the small intestine can be accelerated by the addition of sow colostrum or porcine IgG in quantities sufficient to stimulate endocytosis. These effects disappear when the amount of human IgG administered is itself sufficient to fully stimulate endocytosis.4. Preferential transport of porcine over human IgG can be demonstrated when both are given as a single solution to individual pigs. The degree of preference is, however, small in relation to the total amount of immunoglobulin transported.5. The initial formation of endocytotic vacuoles in the pig intestine seems, unlike the situation in rats and mice, to provide a major route for the trans-cellular movement of macromolecules including immunoglobulins. Present evidence suggests that, though sow colostrum can on occasion stimulate such transport, it does so merely by acting as a protein-containing solution to increase the amount of endocytosis taking place.