Cost-effectiveness of balloon kyphoplasty and vertebroplasty versus conservative medical management in the USA.

The cost-effectiveness of surgical versus conservative medical management of vertebral compression fractures in the US was analyzed in the context of inpatient versus outpatient treatment. Surgical intervention (balloon kyphoplasty and vertebroplasty) was found to be cost-effective relative to conservative medical management at a US willingness-to-pay threshold. INTRODUCTION: To date, only one published study has evaluated the cost-effectiveness (C/E) of balloon kyphoplasty (BKP) or vertebroplasty (VP) in US Medicare patients with osteoporotic vertebral compression fractures. This study further evaluates the C/E of surgical treatment vs. conservative medical management (CMM), expanding on prior modeling by accounting for quality-adjusted life-years gained. METHODS: A Markov microsimulation model of 1000 patients was constructed. Cost data were based on an analysis of Medicare claims payments, with propensity-score matching performed for BKP and VP vs. controls (CMM). Mortality inputs were based on US life tables, modified to account for age at initial fracture, presence of subsequent fracture(s), and relative risk of mortality by treatment. Separate incremental cost-effectiveness ratios (ICERs) were calculated for BKP and VP in inpatient and outpatient surgical treatment locations to account for individual clinical profiles presenting to each. RESULTS: The discounted ICER for inpatient BKP vs. CMM was $43,455 per QALY gained; for outpatient BKP vs. CMM, $10,922; for inpatient VP vs. CMM, $39,774; and for outpatient VP vs. CMM, $12,293. Probabilistic sensitivity analysis confirmed that both BKP and VP would be considered C/E vs. CMM at a US willingness-to-pay (WTP) threshold of $50,000/QALY in 80% and 100% of 500 model simulations, respectively. The most sensitive parameters included quality of life estimates and hazard ratios for mortality. CONCLUSION: While VP and BKP are more expensive treatment options than CMM in the short term, model results suggest interventional treatment is cost-effective, among patients eligible for surgery, at a US WTP threshold. This conclusion supports those from economic analyses conducted in EU-member countries.

Using Qualitative Disease Risk Analysis for Herpetofauna Conservation Translocations Transgressing Ecological and Geographical Barriers.

Through the exploration of disease risk analysis methods employed for four different UK herpetofauna translocations, we illustrate how disease hazards can be identified, and how the risk of disease can be analysed. Where ecological or geographical barriers between source and destination sites exist, parasite populations are likely to differ in identity or strain between the two sites, elevating the risk from disease and increasing the number and category of hazards requiring analysis. Simplification of the translocation pathway through the avoidance of these barriers reduces the risk from disease. The disease risk analysis tool is intended to aid conservation practitioners in decision making relating to disease hazards prior to implementation of a translocation.

Initial observations on using magnesium metal in peripheral nerve repair.

Biodegradable magnesium metal filaments placed inside biodegradable nerve conduits might provide the physical guidance support needed to improve the rate and extent of regeneration of peripheral nerves across injury gaps. In this study, we examined basic issues of magnesium metal resorption and biocompatibility by repairing sub-critical size gap injuries (6 mm) in one sciatic nerve of 24 adult male Lewis rats. Separated nerve stumps were connected with poly(caprolactone) nerve conduits, with and without magnesium filaments (0.25 mm diameter, 10 mm length), with two different conduit filler substances (saline and keratin hydrogel). At 6 weeks after implantation, magnesium degradation was examined by micro-computed tomography and histological analyses. Magnesium degradation was significantly greater when the conduits were filled with an acidic keratin hydrogel than with saline (p < 0.05). But magnesium filaments in some animals remained intact for 6 weeks. Using histological and immunocytochemical analyses, good biocompatibility of the magnesium implants was observed at 6 weeks, as shown by good development of regenerating nerve mini-fascicles and only mild inflammation in tissues even after complete degradation of the magnesium. Nerve regeneration was not interrupted by complete magnesium degradation. An initial functional evaluation, determination of size recovery of the gastrocnemius muscle, showed a slight improvement due to magnesium with the saline but not the keratin filler, compared with respective control conduits without magnesium. These results suggest that magnesium filament implants have the potential to improve repair of injured peripheral nerve defects in this rodent model.

LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression.

RNA-binding proteins (RBPs) bind to and post-transcriptionally regulate the stability of mRNAs. La-related protein 1 (LARP1) is a conserved RBP that interacts with poly-A-binding protein and is known to regulate 5'-terminal oligopyrimidine tract (TOP) mRNA translation. Here, we show that LARP1 is complexed to 3000 mRNAs enriched for cancer pathways. A prominent member of the LARP1 interactome is mTOR whose mRNA transcript is stabilized by LARP1. At a functional level, we show that LARP1 promotes cell migration, invasion, anchorage-independent growth and in vivo tumorigenesis. Furthermore, we show that LARP1 expression is elevated in epithelial cancers such as cervical and non-small cell lung cancers, where its expression correlates with disease progression and adverse prognosis, respectively. We therefore conclude that, through the post-transcriptional regulation of genes such as mTOR within cancer pathways, LARP1 contributes to cancer progression.

Sexual activity and functioning in ovarian cancer survivors: an internet-based evaluation.

OBJECTIVES: Sexual dysfunction is a known complication of treatment for many cancers, but there have been relatively few studies investigating outcomes for ovarian cancer survivors. We have previously reported that women treated for ovarian cancer experience persistent psychological and physical problems. Sexual functioning was highlighted as a significant factor and we sought to investigate this further. METHODS: Women were invited to complete a questionnaire using both paper and online response formats. A validated tool, the Sexual Activity Questionnaire, was used to obtain information from women following a diagnosis of ovarian cancer. RESULTS: Across all responders (n = 102, mean age 51.3 years), 63% of women reported their ovarian cancer diagnosis had negatively changed their sex life. The most common reasons given for an absence of sexual activity were a lack of interest in sex, physical problems that prevented sex or no partner. Of the 46% of responders who stated they were sexually active, 77% reported pain or discomfort during intercourse and 87% described vaginal dryness. CONCLUSION: For the majority of women, treatment for ovarian cancer negatively impacts on their sex lives. Many of the symptoms described by participants are potentially reversible and clinicians should be open to raising the issue of sexual functioning with their patients.

A novel application for bolus remifentanil: blunting the hemodynamic response to Mayfield skull clamp placement.

OBJECTIVE: Neurosurgery often requires skull immobilization with a Mayfield clamp, which often causes brief intense nociceptive stimulation, hypertension and tachycardia. Blunting this response may help prevent increased intracranial pressure, cerebral aneurysm or vascular malformation rupture, and/or myocardial stress. While various interventions have been described to blunt this response, no reports have compared administration of a propofol versus a remifentanil bolus. METHODS: We retrospectively analyzed the hemodynamic response to Mayfield placement in over 800 patients who received a prior propofol or remifentanil bolus from 2004 to 2010. RESULTS: Patients who received remifentanil experienced a 55% smaller increase in heart rate (p < 0.0001) and a 40% smaller increase in systolic blood pressure (p < 0.0001) after Mayfield placement than patients who received propofol. These data were retrospectively obtained from patients who were not randomized to receive remifentanil versus propofol, and hence these data could be subject to possible confounding. Nonetheless, these differences remained significant after multivariate analysis for possible confounding variables. CONCLUSIONS: Thus, a remifentanil bolus is more effective than a propofol bolus in blunting hemodynamic responses to Mayfield placement, and possibly for other short, intense nociceptive stimuli.

Internal or external wall diameter for abdominal aortic aneurysm screening?

INTRODUCTION: The national abdominal aortic aneurysm (AAA) screening programme measures internal wall diameter; however, current UK intervention criteria use external wall diameter. Our aim was to determine the clinical significance of the difference between these two measurements. PATIENTS AND METHODS: Fifty patients on an aneurysm surveillance programme were ultrasound scanned by two experienced vascular scientists, blinded to the other's results. Maximum anteroposterior internal wall and maximum anteroposterior external wall diameters were measured. RESULTS: The median difference between internal and external diameter was 6 mm (IQR 6-7) for scientist 1 and 7 mm (IQR 5-8) for scientist 2. This was statistically significant (P < 0.0002). External wall diameter displayed less interobserver variability (3 mm vs 6 mm). CONCLUSIONS: Screening measurements underestimate aneurysm size by 6 mm and display greater variability in comparison to external wall measurements. These findings should be understood to prevent a delay in the detection and treatment of AAAs.

The Short-Term Effect of Whole Body Vibration Training on Sprint Start Performance in Collegiate Athletes.

Whole body vibration (WBV) is characterized by a vibratory stimulus emitted throughout the body through the use of a vibrating platform on which the subject stands. Studies have shown over 30% increases in maximal explosive strength such as maximal speed biceps curl as well as increases in maximum dynamic force such as maximal sitting bench pull as the result of vibration. The purpose of this study was to investigate the effects of short term whole-body vibration on sprint starts among collegiate track athletes. On the first day eleven subjects were randomly assigned to either a non-vibration or vibration group for initial testing. The vibration group used whole body vibration along with their normal warm-up routine while the non-vibration group did not. Force measurements were taken where the starting blocks were placed using a force plate embedded under the track surface following the warm up. One week later the groups alternated. The results were then compared between vibration and non-vibration groups for individual athletes. The vibration protocol occurred for 60 s at 26 Hz with an amplitude of 4mm on a Galileo 2000 platform. Repeated measures analysis of the variance showed peak resultant force was 6% greater when the vibration platform was utilized prior to the start (p=0.013). Further research is needed to determine whether any meaningful differences exist in sprint start velocity as a result of WBV. There were no observed differences in the 30m sprint times.

Early identification of at-risk nursing students: a student support model.

Due to the shortage of nurses in the health care industry, colleges offering associate-degree nursing programs are beginning to pay more attention to attrition and the factors contributing to success. Alogistic regression model was used to explain the cognitive and noncognitive variables that contribute to success in a nursing fundamentals course. Although much work is necessary to fully understand first-semester nursing students' retention and success, an early identification model is explored to better support students as they enter associate-degree nursing programs.

Sunitinib in the management of gastrointestinal stromal tumours (GISTs).

AIMS: Gastrointestinal stromal tumours (GISTs) are rare mesenchymal neoplasms of the gut with a 5-year survival of approximately 50%. Surgery remains the treatment of choice in resectable disease, with conventional chemotherapy largely ineffective. Over 90% of GIST possesses mutations in the c-KIT oncogene, producing an overactive tyrosine kinase, which may be driving the malignant process. Imatinib inhibits the aberrant tyrosine kinase and imatinib therapy in metastatic disease has shown significant clinical benefit. However, resistance typically develops within 2 years, with the need for further therapy. This article aims to introduce the reader to a new development in cancer therapeutics. METHODS: A literature search was performed using the MEDLINE database to identify publications relevant to the review. References within these articles were used to expand the search. Abstracts from recent ASCO symposia were hand searched for relevant articles. FINDINGS: Sunitinib (SU11248) is a novel multi-targeted tyrosine kinase inhibitor with activity not only against the receptor tyrosine kinase product of c-KIT but also other cell-signalling pathways that may be relevant in GIST; FLT3, platelet-derived growth receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR). Two Phase II trials and one Phase III trial have investigated the activity of sunitinib against imatinib-resistant GIST. Early results showed significant benefits in time to disease progression that led to licensing of the drug in America and more recently in Europe. A Phase III trial comparing dose-increased imatinib and sunitinib in progressed GIST is currently planned. CONCLUSIONS: Initial clinical results with sunitinib are promising and suggest a future role. Further studies are needed before sunitinib can be recommended for the routine treatment of imatinib-refractory GIST.

Whole body vibration and dynamic restraint.

The purpose of this study was to identify changes due to whole body vibration in peroneus longus (PL) activation following ankle inversion perturbation. Participants were 22 (age 22.1 +/- 1.8 yrs, ht 168.8 +/- 8.2 cm, mass 65.5 +/- 11.2 kg) physically active male and female students with no recent history of lower extremity injury. Measurements of PL electromechanical delay (EMD), reaction time, and muscle activation were collected from two groups (WBV and control) over 3 time intervals (pretreatment, posttreatment, and 30 min posttreatment). Two-way ANOVAs were used to compare groups over time for all dependent variables. No group x time interactions were detected (p < 0.05) for any of the dependent variables. Whole body vibration did not alter PL EMD, reaction time, peak EMG, or average EMG. The use of WBV for enhancing ankle dynamic stability was not supported by this study. However, more data are needed to determine if WBV is an effective intervention in other areas of injury prevention or rehabilitation. These data were not consistent with the hypothesis that WBV enhances muscle spindle sensitivity.

Blood pressure-measuring devices in rural South Africa: an audit conducted by the SASPI team in the Agincourt field site.

BACKGROUND: Cardiovascular disease is an important cause of morbidity and mortality in South Africa. The Southern Africa Stroke Prevention Initiative (SASPI) found a high prevalence of stroke in the rural Agincourt subdistrict, Limpopo province. Hypertension is the commonest vascular risk factor in our population and it is essential that primary care services be adequately equipped to detect and treat hypertension. The aim of this study was to assess the number, accuracy and working condition of blood pressure measuring devices (BMD) in the clinics that serve the field site, and to assess the clinic sisters' perceptions of the availability of antihypertensive medication and aspirin. METHODS: In each of the clinics serving the site we assessed the BMDs and cuffs using the following criteria: general condition, bladder size, state of rubber components, operation of the inlet valve and control of valve operation. The legibility of the gauge, level and condition of the mercury, and the condition of the glass tube were checked when relevant. The performance of the BMD was then assessed both with the cuff used in the clinic and with a new functioning cuff, against an accurate mercury sphygmomanometer. By interviewing the clinic sister we could assess the availability of antihypertensive medication and aspirin, as well as the state of the drug delivery system. RESULTS: All BMDs were mercury sphygmomanometers. Four clinics had one BMD each, one clinic had two, and one clinic had four. In one clinic the device was not functional at all until the study cuff was used. None of the clinics had spare cuffs and only one clinic had access to a large cuff. Nine out of 10 (90%) cuffs tested had unsatisfactory valve function, and none was of the size recommended by the guidelines. Although the condition of the mercury was only considered satisfactory in 40% of BMDs, once a new cuff had been fitted to the BMDs all of them were accurate to within 4 mmHg between 50 and 250 mmHg. Fifty per cent of clinic sisters felt they always had sufficient stock of hydrochlorothiazide and alpha-methyldopa, but the supply of more expensive medication was less reliable. Only one clinic always had sufficient aspirin. CONCLUSION: Although none of the primary care clinics had fully functioning BMDs, almost all the defects related to malfunctioning and inappropriately sized cuffs, which would be inexpensive to repair or replace. A procedure for routine servicing or replacement of both BMDs and cuffs is needed, as well as optimisation of medication delivery to remote areas.

Characterization and cDNA cloning of three major proteins from pharate pupal cuticle of Manduca sexta.

Three proteins, MsCP20, MsCP27 and MsCP36, that are secreted in greatest quantity into the pharate pupal cuticle of Manduca sexta ( Hopkins et al., 2000) were purified and their amino acid sequences determined by mass spectrometry and Edman degradation. Although these proteins become sclerotized and insoluble in the pupal exoskeleton, their sequences contain features characteristic for proteins occurring in less sclerotized pliable cuticles, such as arthrodial membranes and soft larval cuticles. These proteins carry a secondary modification attached to a threonine residue, presumably an O-linked sugar moiety. cDNA clones of the genes for MsCP20, MsCP27 and MsCP36 were constructed from pharate pupal integument RNA. Close agreement was found between the amino acid sequences determined by Edman degradation and sequences deduced from the cDNA clones. The molecular masses determined by protein sequencing for MsCP20, MsCP27, and MsCP36 were 17713, 17448, and 29582 Da, respectively, in close agreement with the masses deduced from the corresponding cDNA clones (17711, 17410, and 29638 Da). Temporal expression analysis indicates that MsCP20 and MsCP36 transcripts are present at low levels early in the fifth larval stadium, followed by a large increase in abundance prior to pupal ecdysis. MsCP27 was not detected during development of the fifth larval instar, but its transcript, like those of MsCP20 and MsCP36, increased to a peak level just before pupal ecdysis. Only the MsCP36 transcript was detected in adults. These results support the hypothesis that these proteins are synthesized by the epidermis and are subsequently deposited into the cuticle during the larval-pupal transformation of M. sexta where they become sclerotized in the formation of pupal exocuticle.

AMP-activated protein kinase regulation of fatty acid oxidation in the ischaemic heart.

The heart relies predominantly on a balance between fatty acids and glucose to generate its energy supply. There is an important interaction between the metabolic pathways of these two substrates in the heart. When circulating levels of fatty acids are high, fatty acid oxidation can dominate over glucose oxidation as a source of energy through feedback inhibition of the glucose oxidation pathway. Following an ischaemic episode, fatty acid oxidation rates increase further, resulting in an uncoupling between glycolysis and glucose oxidation. This uncoupling results in an increased proton production, which worsens ischaemic damage. Since high rates of fatty acid oxidation can contribute to ischaemic damage by inhibiting glucose oxidation, it is important to maintain proper control of fatty acid oxidation both during and following ischaemia. An important molecule that controls myocardial fatty acid oxidation is malonyl-CoA, which inhibits uptake of fatty acids into the mitochondria. The levels of malonyl-CoA in the heart are controlled both by its synthesis and degradation. Three enzymes, namely AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and malonyl-CoA decarboxylase (MCD), appear to be extremely important in this process. AMPK causes phosphorylation and inhibition of ACC, which reduces the production of malonyl-CoA. In addition, it is suggested that AMPK also phosphorylates and activates MCD, promoting degradation of malonyl-CoA levels. As a result malonyl-CoA levels can be dramatically altered by activation of AMPK. In ischaemia, AMPK is rapidly activated and inhibits ACC, subsequently decreasing malonyl-CoA levels and increasing fatty acid oxidation rates. The consequence of this is a decrease in glucose oxidation rates. In addition to altering malonyl-CoA levels, AMPK can also increase glycolytic rates, resulting in an increased uncoupling of glycolysis from glucose oxidation and an enhanced production of protons and lactate. This decreases cardiac efficiency and contributes to the severity of ischaemic damage. Decreasing the ischaemic-induced activation of AMPK or preventing the downstream decrease in malonyl-CoA levels may be a therapeutic approach to treating ischaemic heart disease.

Development of a larval bioassay for susceptibility of cat fleas (Siphonaptera: Pulicidae) to imidacloprid.

Strategies for controlling cat fleas, Ctenocephalidesfelisfelis (Bouché), have undergone dramatic changes in the past 5 yr. With the advent of on-animal treatments with residual activity the potential for the development of insecticide resistance increases. A larval bioassay was developed to determine the baseline susceptibility of field-collected strains of cat fleas to imidacloprid. All four laboratory strains tested showed a similar level of susceptibility to imidacloprid. Advantages of this bioassay are that smaller numbers of fleas are required because flea eggs are collected for the test. Insect growth regulators and other novel insecticides can also be evaluated. Using a discriminating dose, the detection of reduced susceptibility in field strains can be determined with as few as 40 eggs.

New inhibitors of the thioredoxin-thioredoxin reductase system based on a naphthoquinone spiroketal natural product lead.

Natural products of the naphthoquinone spiroketal structural type served as lead structures for the development of novel inhibitors of the thioredoxin-thioredoxin reductase redox system. The most potent compound in this series inhibited thioredoxin with an IC(50) of 350 nM, and many derivatives showed low micromolar activities for growth inhibition against two breast cancer cell lines.

Solid-phase library synthesis of alkoxyprolines.

The library synthesis of alkoxyprolines was achieved using an acid-stable, nucleophile-cleavable solid support. A hydroxythiophenol linker derived from Merrifield resin was esterified with the corresponding ethers of BOC-hydroxyproline. Removal of the BOC protecting group with trifluoroacetic acid followed by acylation gave solid-supported hydroxyproline derivatives. Cleavage from the solid support with excess primary amines or excess secondary amines followed by purification of the crude products from the excess amine by supported liquid-liquid extraction gave the alkoxyproline library in high purity.

Lepidopteran peritrophic membranes and effects of dietary wheat germ agglutinin on their formation and structure.

Peritrophic membrane (PM) structure and the effects of dietary wheat germ agglutinin (WGA) on PM formation were studied in larvae of the European corn borer (ECB), Ostrinia nubilalis, and the tobacco hornworm (THW), Manduca sexta. Growth of ECB was strongly inhibited by low amounts of WGA in the diet (0.05%), whereas THW was not affected by amounts of up to 2%. In ECB larvae, chitin microfibrils were secreted to form an orthogonal network within the apical region of the anterior midgut microvilli. The network then moved to the tips of the microvilli where proteinacious matrix was added prior to delamination of a single PM into the lumen to enclose the food bolus. Multiple PMs rapidly appeared as the food moved posteriorly and some of these became greatly thickened in the middle and posterior regions of the midgut. WGA in the diet caused hypersecretion of unorganized PM in the anterior midgut lumen, disintegration of microvilli, and cessation of feeding. It was also shown to bind to both the chitinous network and to several PM proteins, perhaps causing voids in the PM and sparse matrix material. This allowed the passage of food particles through a defective PM into the ectoperitrophic space and penetration into the microvillar brush border. Stimulation of PM secretion and cessation of feeding may have been a response to damage to the brush border. Unlike ECB, the chitinous network of THW is a randomly organized felt-like structure embedded in a proteinaceous matrix. This PM is secreted as a thin multilayered structure in the anterior region of the midgut, but multiple and thickened PMs occur in the middle and posterior lumens of the midgut. THW tolerated high amounts of WGA in its diet with no disruption of PM formation or inhibition of growth. WGA did accumulate as large masses embedded in the PM, but caused no voids that would allow the penetration of food particles and subsequent damage to the brush border. Therefore, differences in PM formation and structure between ECB and THW appeared to affect how WGA interacts with chitinous and proteinaceous components of the PM and subsequent effects on larval feeding and growth.

Spectroscopy of UO(2)Cl(4)(2)(-) in basic aluminum chloride-1-ethyl-3-methylimidazolium chloride.

The optical absorption, emission, FT Raman, one-photon excitation, two-photon excitation, and luminescence lifetime measurements are reported for UO(2)Cl(4)(2)(-) in 40:60 AlCl(3)-EMIC (where EMIC identical with 1-ethyl-3-methylimidazolium chloride), a room-temperature ionic liquid. Comparison of the spectra with previous results from single crystals containing UO(2)Cl(4)(2)(-) allowed the characterization of four ground-state vibrational frequencies, two excited-state vibrational frequencies, and the location of eight electronic excited-state energy levels. The vibrational frequencies and electronic energy levels are found to be consistent with the UO(2)Cl(4)(2)(-) ion. Comparison of the one-photon and two-photon excitation spectra, and the relative intensities of the transitions in the emission spectrum indicate that the center of symmetry is perturbed by an interaction with the solvent.

The influence of arm length asymmetry and base substitution on the activity of the 10-23 DNA enzyme.

A small oligodeoxyribonucleotide derived from in vitro selection has been shown to be capable of efficient sequence-specific cleavage of RNA at purine-pyrimidine junctions. As the reaction readily takes place under simulated physiologic conditions, this molecule described as the 10-23 general purpose RNA-cleaving DNA enzyme, has potential as a therapeutic agent. To further explore the character of this prototype, we examined the influence of base substitution and binding arm length asymmetry on its RNA cleaving activity. Surprisingly, substitution of the proximal nucleotide on the 3'-arm, to allow nonstandard Watson-Crick interactions, was found in some instances to improve the cleavage reaction rate. Although the identity of the unpaired purine in the RNA substrate cleavage site was found to have only a subtle influence on the rate of catalysis, with a slight decrease observed when a G at this position was changed to an A, nucleotide substitution (G to C) in the core motif at position 14 was found to completely abolish catalysis. The effect of arm length reduction varied with RNA substrate sequence and extent of helix asymmetry. Where the cleavage rate of one substrate was impaired by truncation of the deoxyribozymes 5'-arm (6 bp), the same modification in reactions with a different sequence produced a rate enhancement. Truncation of the 3'-arm, however, had no effect on the reaction rate of the one substrate tested yet nearly halved the cleavage rate in another substrate.