An evaluation of continuous subcutaneous infusions across seven NHS acute hospitals: is there potential for 48-hour infusions?

BACKGROUND: Continuous subcutaneous infusions (CSCIs) are commonly used in the United Kingdom as a way of administering medication to patients requiring symptom control when the oral route is compromised. These infusions are typically administered over 24 h due to currently available safety data. The ability to deliver prescribed medication by CSCI over 48 h may have numerous benefits in both patient care and health service resource utilisation. This service evaluation aims to identify the frequency at which CSCI prescriptions are altered at NHS Acute Hospitals. METHODS: Pharmacists or members of palliative care teams at seven acute NHS hospitals recorded anonymised prescription data relating to the drug combination(s), doses, diluent and compatibility of CSCIs containing two or more drugs on a daily basis for a minimum of 2 days, to a maximum of 7 days. RESULTS: A total of 1301 prescriptions from 288 patients were recorded across the seven sites, yielding 584 discrete drug combinations. Of the 584 combinations, 91% (n = 533) included an opioid. The 10 most-common CSCI drug combinations represented 37% of the combinations recorded. Median duration of an unchanged CSCI prescription across all sites was 2 days. CONCLUSION: Data suggests medication delivered by CSCI over 48 h may be a viable option. Before a clinical feasibility study can be undertaken, a pharmacoeconomic assessment and robust chemical and microbiological stability data will be required, as will the assessment of the perceptions from clinical staff, patients and their families on the acceptability of such a change in practice.

Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers.

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, PFDR<0.05, kE=2198, x=-30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, PFDR<0.05, kE=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.

Deletion of Sod1 in Motor Neurons Exacerbates Age-Related Changes in Axons and Neuromuscular Junctions in Mice.

Whole-body knock-out of Cu,Zn superoxide dismutase (Sod1KO) results in accelerated, age-related loss of muscle mass and function associated with neuromuscular junction (NMJ) breakdown similar to sarcopenia. In order to determine whether altered redox in motor neurons underlies this phenotype, an inducible neuron-specific deletion of Sod1 (i-mnSod1KO) was compared with wild-type (WT) mice of different ages (adult, mid-age, and old) and whole-body Sod1KO mice. Nerve oxidative damage, motor neuron numbers and structural changes to neurons and NMJ were examined. Tamoxifen-induced deletion of neuronal Sod1 from two months of age. No specific effect of a lack of neuronal Sod1 was seen on markers of nerve oxidation (electron paramagnetic resonance of an in vivo spin probe, protein carbonyl, or protein 3-nitrotyrosine contents). i-mnSod1KO mice showed increased denervated NMJ, reduced numbers of large axons and increased number of small axons compared with old WT mice. A large proportion of the innervated NMJs in old i-mnSod1KO mice displayed a simpler structure than that seen in adult or old WT mice. Thus, previous work showed that neuronal deletion of Sod1 induced exaggerated loss of muscle in old mice, and we report that this deletion leads to a specific nerve phenotype including reduced axonal area, increased proportion of denervated NMJ, and reduced acetyl choline receptor complexity. Other changes in nerve and NMJ structure seen in the old i-mnSod1KO mice reflect aging of the mice.

Skeletal muscle transcriptomics identifies common pathways in nerve crush injury and ageing.

Motor unit remodelling involving repeated denervation and re-innervation occurs throughout life. The efficiency of this process declines with age contributing to neuromuscular deficits. This study investigated differentially expressed genes (DEG) in muscle following peroneal nerve crush to model motor unit remodelling in C57BL/6 J mice. Muscle RNA was isolated at 3 days post-crush, RNA libraries were generated using poly-A selection, sequenced and analysed using gene ontology and pathway tools. Three hundred thirty-four DEG were found in quiescent muscle from (26mnth) old compared with (4-6mnth) adult mice and these same DEG were present in muscle from adult mice following nerve crush. Peroneal crush induced 7133 DEG in muscles of adult and 699 DEG in muscles from old mice, although only one DEG (ZCCHC17) was found when directly comparing nerve-crushed muscles from old and adult mice. This analysis revealed key differences in muscle responses which may underlie the diminished ability of old mice to repair following nerve injury.

Effect of xanthine oxidase-generated extracellular superoxide on skeletal muscle force generation.

Skeletal muscle contractions increase superoxide anion in skeletal muscle extracellular space. We tested the hypotheses that 1) after an isometric contraction protocol, xanthine oxidase (XO) activity is a source of superoxide anion in the extracellular space of skeletal muscle and 2) the increase in XO-derived extracellular superoxide anion during contractions affects skeletal muscle contractile function. Superoxide anion was monitored in the extracellular space of mouse gastrocnemius muscles by following the reduction of cytochrome c in muscle microdialysates. A 15-min protocol of nondamaging isometric contractions increased the reduction of cytochrome c in microdialysates, indicating an increase in superoxide anion. Mice treated with the XO inhibitor oxypurinol showed a smaller increase in superoxide anions in muscle microdialysates following contractions than in microdialysates from muscles of vehicle-treated mice. Intact extensor digitorum longus (EDL) and soleus muscles from mice were also incubated in vitro with oxypurinol or polyethylene glycol-tagged Cu,Zn-SOD. Oxypurinol decreased the maximum tetanic force produced by EDL and soleus muscles, and polyethylene glycol-tagged Cu,Zn-SOD decreased the maximum force production by the EDL muscles. Neither agent influenced the rate of decline in force production when EDL or soleus muscles were repeatedly electrically stimulated using a 5-min fatiguing protocol (stimulation at 40 Hz for 0.1 s every 5 s). Thus these studies indicate that XO activity contributes to the increased superoxide anion detected within the extracellular space of skeletal muscles during nondamaging contractile activity and that XO-derived superoxide anion or derivatives of this radical have a positive effect on muscle force generation during isometric contractions of mouse skeletal muscles.

Vitamin D deficiency is associated with tuberculosis disease in British children.

BACKGROUND: Basic science, epidemiological and interventional research supports a link between vitamin D and tuberculosis (TB) immunity, infection and disease. We evaluated the association between vitamin D levels and TB infection and disease in UK children recruited to the National Institute for Health Research IGRA Kids Study (NIKS).METHODS: Children presenting between 2011 and 2014 were eligible if they had history of exposure to an adult case with sputum smear/culture-positive TB, or were referred and diagnosed with TB disease. Children were assessed at baseline and at 6-8 weeks for immunological evidence of TB infection (interferon-gamma release assay and/or tuberculin skin test) and evidence of TB disease. Some centres routinely measured total 25-hydroxy vitamin D (25-OHD) levels.RESULTS: A total of 166 children were included. The median 25-OHD levels were higher in non-infected children (45.5 nmol/l) than in those with tuberculous infection (36.2 nmol/l) and TB disease (20.0 nmol/l). The difference between TB infection and disease was statistically significant (P < 0.001). By logistic regression, lower vitamin D levels were associated with TB disease among participants with infection or disease, with no evidence of confounding by age, sex, bacille Calmette-Guérin vaccination status, ethnicity, non-contact referral, season or centre.CONCLUSION: Children with TB disease had lower vitamin D levels than children with infection. Implications for prevention and treatment remain to be established.

HyPer2 imaging reveals temporal and heterogeneous hydrogen peroxide changes in denervated and aged skeletal muscle fibers in vivo.

To determine the role of denervation and motor unit turnover in the age-related increase in skeletal muscle oxidative stress, the hydrogen peroxide (H2O2) specific, genetically-encoded, fluorescent cyto-HyPer2 probe was expressed in mouse anterior tibialis (AT) muscle and compared with ex vivo measurements of mitochondrial oxidant generation. Crush of the peroneal nerve induced increased mitochondrial peroxide generation, measured in permeabilised AT fibers ex vivo and intra vital confocal microscopy of cyto-HyPer2 fluorescence showed increased cytosolic H2O2 in a sub-set (~24%) of individual fibers associated with onset of fiber atrophy. In comparison, mitochondrial peroxide generation was also increased in resting muscle from old (26 month) mice compared with adult (6-8 month) mice, but no age effect on fiber cytosolic H2O2 in vivo was seen. Thus ageing is associated with an increased ability of muscle fibers to maintain cytosolic redox homeostasis in the presence of denervation-induced increase in mitochondrial peroxide generation.

Free radical generation by skeletal muscle of adult and old mice: effect of contractile activity.

Oxidative modification of cellular components may contribute to tissue dysfunction during aging. In skeletal muscle, contractile activity increases the generation of reactive oxygen and nitrogen species (ROS). The question of whether contraction-induced ROS generation is further increased in skeletal muscle of the elderly is important since this influences recommendations on their exercise participation. Three different approaches were used to examine whether aging influences contraction-induced ROS generation. Hind limb muscles of adult and old mice underwent a 15-min period of isometric contractions and we examined ROS generation by isolated skeletal muscle mitochondria, ROS release into the muscle extracellular fluid using microdialysis techniques, and the muscle glutathione and protein thiol contents. Resting skeletal muscle of old mice compared with adult mice showed increased ROS release from isolated mitochondria, but no changes in the extracellular levels of superoxide, nitric oxide, hydrogen peroxide, hydroxyl radical activity or muscle glutathione and protein thiol contents. Skeletal muscle mitochondria isolated from both adult and old mice after contractile activity showed significant increases in hydrogen peroxide release compared with pre-contraction values. Contractions increased extracellular hydroxyl radical activity in adult and old mice, but had no significant effect on extracellular hydrogen peroxide or nitric oxide in either group. In adult mice only, contractile activity increased the skeletal muscle release of superoxide. A similar decrease in muscle glutathione and protein thiol contents was seen in adult and old mice following contractions. Thus, contractile activity increased skeletal muscle ROS generation in both adult and old mice with no evidence for an age-related exacerbation of ROS generation.

Genetic modification of the manganese superoxide dismutase/glutathione peroxidase 1 pathway influences intracellular ROS generation in quiescent, but not contracting, skeletal muscle cells.

Increased amounts of reactive oxygen species (ROS) are generated by skeletal muscle during contractile activity, but their intracellular source is unclear. The oxidation of 2',7'-dichlorodihydrofluorescein (DCFH) was examined as an intracellular probe for reactive oxygen species in skeletal muscle myotubes derived from muscles of wild-type mice and mice that were heterozygous knockout for manganese superoxide dismutase (Sod2(+/-)), homozygous knockout for glutathione peroxidase 1 (GPx1(-/-)), or MnSOD transgenic overexpressors (Sod2-Tg). Myoblasts were stimulated to fuse and loaded with DCFH 5-7 days later. Intracellular DCF epifluorescence was measured and myotubes were electrically stimulated to contract for 15 min. Quiescent myotubes with decreased MnSOD or GPx1 showed a significant increase in the rate of DCFH oxidation whereas those with increased MnSOD did not differ from wild type. Following contractions, myotubes from all groups showed an equivalent increase in DCF fluorescence. Thus the oxidation of DCFH in quiescent skeletal muscle myotubes is influenced by the content of enzymes that regulate mitochondrial superoxide and hydrogen peroxide content. In contrast, the increase in DCFH oxidation following contractions was unaffected by reduced or enhanced MnSOD or absent GPx1, indicating that reactive oxygen species produced by contractions were predominantly generated by nonmitochondrial sources.

Adaptive responses of mouse skeletal muscle to contractile activity: The effect of age.

This study has characterised the time course of two major transcriptional adaptive responses to exercise (changes in antioxidant defence enzyme activity and heat shock protein (HSP) content) in muscles of adult and old male mice following isometric contractions and has examined the mechanisms involved in the age-related reduction in transcription factor activation. Muscles of B6XSJL mice were subjected to isometric contractions and analysed for antioxidant defence enzyme activities, heat shock protein content and transcription factor DNA binding activity. Data demonstrated a significant increase in superoxide dismutase (SOD) and catalase activity and HSP content of muscles of adult mice following contractile activity which was associated with increased activation of the transcription factors, nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1) and heat shock factor (HSF) following contractions. Significant increases in SOD and catalase activity and heat shock cognate (HSC70) content were seen in quiescent muscles of old mice. The increase in antioxidant defence enzyme activity following contractile activity seen in muscles of adult mice was not seen in muscles of old mice and this was associated with a failure to fully activate NF-kappaB and AP-1 following contractions. In contrast, although the production of HSPs was also reduced in muscles of old mice following contractile activity compared with muscles of adult mice following contractions, this was not due to a gross reduction in the DNA binding activity of HSF.

Nitric oxide availability is increased in contracting skeletal muscle from aged mice, but does not differentially decrease muscle superoxide.

Reactive oxygen and nitrogen species have been implicated in the loss of skeletal muscle mass and function that occurs during aging. Nitric oxide (NO) and superoxide are generated by skeletal muscle and where these are generated in proximity their chemical reaction to form peroxynitrite can compete with the superoxide dismutation to hydrogen peroxide. Changes in NO availability may therefore theoretically modify superoxide and peroxynitrite activities in tissues, but published data are contradictory regarding aging effects on muscle NO availability. We hypothesised that an age-related increase in NO generation might increase peroxynitrite generation in muscles from old mice, leading to an increased nitration of muscle proteins and decreased superoxide availability. This was examined using fluorescent probes and an isolated fiber preparation to examine NO content and superoxide in the cytosol and mitochondria of muscle fibers from adult and old mice both at rest and following contractile activity. We also examined the 3-nitrotyrosine (3-NT) and peroxiredoxin 5 (Prx5) content of muscles from mice as markers of peroxynitrite activity. Data indicate that a substantial age-related increase in NO levels occurred in muscle fibers during contractile activity and this was associated with an increase in muscle eNOS. Muscle proteins from old mice also showed an increased 3-NT content. Inhibition of NOS indicated that NO decreased superoxide bioavailability in muscle mitochondria, although this effect was not age related. Thus increased NO in muscles of old mice was associated with an increased 3-NT content that may potentially contribute to age-related degenerative changes in skeletal muscle.

Meta-analysis of complication rates of the tubularized incised plate (TIP) repair.

OBJECTIVE: To determine overall complication rates of the tubularized incised plate (TIP) repair and assess the effects of technical modifications, length of follow-up and geographical location of reported results. MATERIALS AND METHODS: A systematic literature search was undertaken, using Medline and Pubmed, in order to identify relevant articles. Random effects models were used to estimate pooled complication rates. Meta-regression was performed for each outcome by using mixed effects models with type of hypospadias (primary distal, primary proximal and secondary) as predictors. RESULTS: Of the 189 articles that were identified, 49 studies (4675 patients) were included in the analysis. Fistula and re-operation rates were significantly higher in secondary repairs (15.5% and 23.3%) compared to primary proximal (10.3% and 12.2%) and primary distal (5.7% and 4.5%) (P = 0.045 and P < 0.001, respectively). Technical modifications reduced fistula rates from 10.3% to 3.3% (P = 0.003) and re-operation rates from 13.6% to 2.8% (P = 0.001). The rate of meatal stenosis was highest in the secondary repairs, with follow-up >1 year (12.7%). Comparison of geographical location showed that complication rates for all but one variable were significantly lower in North America when compared to Europe and the rest of the world. Mean meatal stenosis rates were 1.8% in North America, 3.4% in Europe and 8.2% in the rest of the world (P = 0.002). This remained significant in a multivariable model incorporating repair technique and length of follow-up (P = 0.046). Mean rates of urethral stricture, fistula and re-operation followed a similar pattern (P = 0.045, P = 0.009 and P < 0.001, respectively). Mean follow-up was shortest in the North American group, at 11.9 months, compared to Europe, at 17.8 months, and the rest of the world, at 18.9 months. DISCUSSION: The present meta-analysis has shown that the lowest complication rates for the TIP repair are when it is applied to primary distal hypospadias. Complication rates are higher for all variables when the TIP repair is used for primary proximal hypospadias. Lower complication rates than those reported in this TIP review have been documented in some studies using a staged repair for correction of primary proximal or secondary hypospadias [11,12,68], implying that a staged approach may be superior to the TIP repair in these settings. Documentation of follow-up duration was limited, making assessment of the impact of length of follow-up difficult. Geographical location had a noticeable effect on outcome, with all but one complication being lower in the North American than the other groups. Mean follow-up was shortest in North America and it is suggested that the short follow-up in the North American studies may have led to under-reporting of late complications. CONCLUSION: The TIP repair has evolved to incorporate modifications that have significantly lowered complications. Higher complication rates are seen with secondary and proximal repairs; however, limited, published long-term data impair a true assessment of outcome.

Mesenchymal Stem Cells and Cutaneous Wound Healing: Current Evidence and Future Potential.

Human skin is a remarkable organ that sustains insult and injury throughout life. The ability of skin to expeditiously repair wounds is paramount to survival. With an aging global population, coupled with a rise in the prevalence of conditions such as diabetes, chronic wounds represent a significant biomedical burden. Mesenchymal stem cells (MSC), a progenitor cell population of the mesoderm lineage, have been shown to be significant mediators in inflammatory environments. Preclinical studies of MSC in various animal wound healing models point towards a putative therapy. This review examines the body of evidence suggesting that MSC accelerate wound healing in both clinical and preclinical studies and also the possible mechanisms controlling its efficacy. The delivery of a cellular therapy to the masses presents many challenges from a safety, ethical, and regulatory point of view. Some of the issues surrounding the introduction of MSC as a medicinal product are also delineated in this review.

Measurement of free radical production by in vivo microdialysis during ischemia/reperfusion injury to skeletal muscle.

Microdialysis techniques have been used to detect hydroxyl radical and superoxide release into the interstitial space of anaesthetized rat anterior tibialis muscles during a period of prolonged (4 h) limb ischemia and subsequent reperfusion. Data indicate that reperfusion of the ischemic skeletal muscle was associated with a large increase in hydroxyl radical activity in the interstitial space, which may contribute to the significant oxidation of muscle glutathione, protein thiols, and lipids also seen in this model. No evidence for release of superoxide into the interstitial space was found during reperfusion, although this was observed during electrically stimulated contractile activity of the rat limb muscle. These data imply that therapeutic approaches aimed at reduction of hydroxyl radical generation in the interstitial fluid are more likely to be beneficial in reduction of skeletal muscle reperfusion injury than approaches designed to scavenge superoxide radicals.

Free radical activity following contraction-induced injury to the extensor digitorum longus muscles of rats.

The purpose of the study was to investigate the role of free radicals in the injury induced by a protocol of repeated pliometric (lengthening) contractions to the extensor digitorum longus (EDL) muscle in situ in rats. Previous data have indicated that prior treatment with the antioxidant polyethylene glycol-superoxide dismutase reduced the damage that was apparent at 3 days following this type of exercise. Three hours and 3 days following the protocol, the magnitude of the semiquinone-derived free radical signal observed by electron spin resonance spectroscopy (ESR) was not different for exercised and non-exercised skeletal muscles. A reduction in the protein thiol content of muscle was evident at 3 h, and was still apparent at 3 days. Three hours after the protocol, the total muscle glutathione content and the percentage in the oxidized form were unchanged, but by 3 days the percentage of muscle glutathione present in the oxidized form was elevated. The susceptibility of muscle to lipid peroxidation in vitro was reduced 3 days after the pliometric contractions. These data indicate that oxidation of protein thiols and glutathione may be involved in the secondary damage following pliometric contractions, but provide no evidence that the species involved were derived from mitochondrial semiquinone radicals.

Reducing parenteral energy and protein intake improves metabolic homeostasis after bone marrow transplantation.

The purpose of this prospective study was to compare the metabolic effects of reducing parenteral energy and protein intake in bone-marrow-transplant (BMT) patients from 150% (hi-TPN group) to 100% (lo-TPN group) basal energy expenditure. Cytotoxic therapy was given on days 1-5, BMT on day 6, and TPN beginning on days 6 or 7. The lo-TPN group exhibited higher serum albumin (38 +/- 0.4 vs 32 +/- 0.4 g/L, P less than 0.01) but similar nitrogen balance (-83 +/- 8 vs -86 +/- 8 mg.kg-1.d-1, P greater than 0.05). Serum Na+ remained greater than 134 +/- 1 mmol/L in the lo-TPN group but fell to 127 +/- 1 mmol/L in the hi-TPN group (P less than 0.001) despite similar Na+ intakes and balances. Serum K+ remained less than 4.4 +/- 0.2 mmol/L in the lo-TPN group but rose to 5.1 +/- 0.1 mmol/L in the hi-TPN group (P less than 0.01) despite similar K+ intakes and balances. Delivering TPN at lower-than-normal rates after BMT appears to minimize Na+ and K+ disturbances and improve serum albumin concentrations without having any adverse effect on nitrogen balance.

In vivo model of muscle pain: quantification of intramuscular chemical, electrical, and pressure changes associated with saline-induced muscle pain in humans.

Intramuscular injection of hypertonic saline is a good model to study human muscle pain (Kellgren 1938). The present study concerns the intramuscular (i.m.) pain mediators in saline-induced muscle pain. In experiment 1, the diffusion of infused hypertonic and isotonic saline (0.5 ml) in m. tibialis anterior was illustrated by magnetic resonance imaging (MRI) in one subject. In experiment 2, six volunteers received four sequential infusions (0.5 ml given at 5 min intervals) of isotonic saline and thereafter four sequential infusions (0.5 ml given at 5 min intervals) of hypertonic saline into m. tibialis anterior. The isotonic and hypertonic saline infusions were computer-controlled and separated by 20 min. The muscle pain intensity was assessed by continuous recordings on a visual analogue scale (VAS). One microdialysis probe was inserted 1 cm from the infusion needle in m. tibialis anterior and another probe in the other m. tibialis anterior. Concentrations of the i.m. sodium, potassium, magnesium, and prostaglandin E2 (PGE2) were assessed from the dialysates. Intramuscular electromyography (EMG) and pressure were assessed in the area of the infused saline. In experiment 1, the infusion of hypertonic and isotonic saline created a visible saline-pool on the MRI scans. These saline-pool volumes were stable and not correlated to the pain scores. In experiment 2, infusion of isotonic saline produced little pain compared to infusion of hypertonic saline. Maximal pain was reported after the first infusion of hypertonic saline and thereafter the pain gradually decreased with subsequent infusions of hypertonic saline. During infusion of hypertonic saline the i.m. sodium and potassium concentrations increased significantly, i.m. magnesium concentration tended to be increased, and the i.m. PGE2 concentration tended to be decreased although these changes were not significant. The i.m. EMG was smaller during and after infusions of hypertonic saline compared with isotonic saline. The i.m. pressure was not different during the infusions of hypertonic and isotonic saline but was increased between the infusions of hypertonic saline. This study has shown that i.m. infusion of hypertonic saline produced a saline-pool, causing the i.m. pressure to increase. Possibly, pain activation and cessation are related to increased intramuscular sodium and potassium content respectively.

How does dystrophin deficiency lead to muscle degeneration?--evidence from the mdx mouse.

The mdx mouse has a defect in the same gene as boys with Duchenne muscular dystrophy, which results in the absence of the protein product, dystrophin. A large number of recent studies have used the mdx mouse model to examine the potential role of dystrophy in normal muscle and the mechanisms by which dystrophin-deficiency leads to myopathy. This review discusses critically the results of these studies and their relevance to understanding the mechanisms by which dystrophin-deficiency leads to muscle necrosis.