The aim of this study was to test the hypothesis that use of tiotropium, a new long-acting anticholinergic bronchodilator, would be associated with sustained reduction in lung hyperinflation and, ...thereby, would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease. A randomised, double-blind, placebo-controlled, parallel-group study was conducted in 187 patients (forced expiratory volume in one second 44 +/- 13% pred): 96 patients received 18 microg tiotropium and 91 patients received placebo once daily for 42 days. Spirometry, plethysmographic lung volumes, cycle exercise endurance and exertional dyspnoea intensity at 75% of each patient's maximal work capacity were compared. On day 42, the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to placebo: vital capacity and inspiratory capacity (IC) increased, with inverse decreases in residual volume and functional residual capacity. Tiotropium increased post-dose exercise endurance time by 105 +/- 40 s (21%) as compared to placebo on day 42. At a standardised time near end-exercise (isotime), IC, tidal volume and minute ventilation all increased, whilst dyspnoea decreased by 0.9 +/- 0.3 Borg scale units. In conclusion, the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise. Resultant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance.
Treatment approaches for relapsed ovarian cancer have evolved over the past decade from a calendar-based decision tree to a patient-oriented biologically driven algorithm. Nowadays, platinum-based ...chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy. The treatment-free interval for platinum is only one of many factors affecting patients' eligibility for platinum re-treatment. Bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (e.g. pleural effusion, ascites). For patients with recurrent high-grade ovarian cancer, which responds to platinum-based treatment, maintenance therapy with a poly(ADP-ribose) polymerase inhibitor can be offered, regardless of the BRCA mutation status. Here we review contemporary decision-making processes in the systemic treatment of relapsed ovarian cancer.
•Platinum-based chemotherapy remains the most active treatment for ovarian cancer.•Platinum should not be withheld after response to last platinum and a treatment-free interval of <6 months.•We propose to move beyond the definition of platinum resistance to a therapy-oriented definition of platinum eligibility.•Platinum-non-eligible ovarian cancer patients are those with progression on or immediately after their last platinum.
This paper introduces and evaluates the second version of the global aerosol-climate model ECHAM-HAM. Major changes have been brought into the model, including new parameterizations for aerosol ...nucleation and water uptake, an explicit treatment of secondary organic aerosols, modified emission calculations for sea salt and mineral dust, the coupling of aerosol microphysics to a two-moment stratiform cloud microphysics scheme, and alternative wet scavenging parameterizations. These revisions extend the model's capability to represent details of the aerosol lifecycle and its interaction with climate. Nudged simulations of the year 2000 are carried out to compare the aerosol properties and global distribution in HAM1 and HAM2, and to evaluate them against various observations. Sensitivity experiments are performed to help identify the impact of each individual update in model formulation. Results indicate that from HAM1 to HAM2 there is a marked weakening of aerosol water uptake in the lower troposphere, reducing the total aerosol water burden from 75 Tg to 51 Tg. The main reason is the newly introduced κ-Köhler-theory-based water uptake scheme uses a lower value for the maximum relative humidity cutoff. Particulate organic matter loading in HAM2 is considerably higher in the upper troposphere, because the explicit treatment of secondary organic aerosols allows highly volatile oxidation products of the precursors to be vertically transported to regions of very low temperature and to form aerosols there. Sulfate, black carbon, particulate organic matter and mineral dust in HAM2 have longer lifetimes than in HAM1 because of weaker in-cloud scavenging, which is in turn related to lower autoconversion efficiency in the newly introduced two-moment cloud microphysics scheme. Modification in the sea salt emission scheme causes a significant increase in the ratio (from 1.6 to 7.7) between accumulation mode and coarse mode emission fluxes of aerosol number concentration. This leads to a general increase in the number concentration of smaller particles over the oceans in HAM2, as reflected by the higher Ångström parameters. Evaluation against observation reveals that in terms of model performance, main improvements in HAM2 include a marked decrease of the systematic negative bias in the absorption aerosol optical depth, as well as smaller biases over the oceans in Ångström parameter and in the accumulation mode number concentration. The simulated geographical distribution of aerosol optical depth (AOD) is better correlated with the MODIS data, while the surface aerosol mass concentrations are very similar to those in the old version. The total aerosol water content in HAM2 is considerably closer to the multi-model average from Phase I of the AeroCom intercomparison project. Model deficiencies that require further efforts in the future include (i) positive biases in AOD over the ocean, (ii) negative biases in AOD and aerosol mass concentration in high-latitude regions, and (iii) negative biases in particle number concentration, especially that of the Aitken mode, in the lower troposphere in heavily polluted regions.
Abstract Bioactive glasses (BG) which contain strontium have the potential to combine the known bone regenerative properties of BG with the anabolic and anti-catabolic effects of strontium cations. ...Here we created a BG series (SiO2 –P2 O5 –Na2 O–CaO) in which 0–100% of the calcium was substituted by strontium and tested their effects on osteoblasts and osteoclasts in vitro . We show that ions released from strontium-substituted BG enhance metabolic activity in osteoblasts. They also inhibit osteoclast activity by both reducing tartrate resistant acid phosphatase activity and inhibiting resorption of calcium phosphate films in a dose-dependent manner. Additionally, osteoblasts cultured in contact with BG show increased proliferation and alkaline phosphatase activity with increasing strontium substitution, while osteoclasts adopt typical resorption morphologies. These results suggest that similarly to the osteoporosis drug strontium ranelate, strontium-substituted BG may promote an anabolic effect on osteoblasts and an anti-catabolic effect on osteoclasts. These effects, when combined with the advantages of BG such as controlled ion release and delivery versatility, may make strontium-substituted BG an effective biomaterial choice for a range of bone regeneration therapies.
This study examined the effects of bronchodilator-induced reductions in lung hyperinflation on breathing pattern, ventilation and dyspnoea during exercise in chronic obstructive pulmonary disease ...(COPD). Quantitative tidal flow/volume loop analysis was used to evaluate abnormalities in dynamic ventilatory mechanics and their manipulation by a bronchodilator. In a randomised double-blind crossover study, 23 patients with COPD (mean +/- SEM forced expiratory volume in one second 42 +/- 3% of the predicted value) inhaled salmeterol 50 microg or placebo twice daily for 2 weeks each. After each treatment period, 2 h after dose, patients performed pulmonary function tests and symptom-limited cycle exercise at 75% of their maximal work-rate. After salmeterol versus placebo at rest, volume-corrected maximal expiratory flow rates increased by 175 +/- 52%, inspiratory capacity (IC) increased by 11 +/- 2% pred and functional residual capacity decreased by 11 +/- 3% pred. At a standardised time during exercise, salmeterol increased IC, tidal volume (VT), mean inspiratory and expiratory flows, ventilation, oxygen uptake (VO2) and carbon dioxide output. Salmeterol increased peak exercise endurance, VO2 and ventilation by 58 +/- 19, 8 +/- 3 and 12 +/- 3%, respectively. Improvements in peak VO2 correlated best with increases in peak VT; increases in peak VT and resting IC were interrelated. The reduction in dyspnoea ratings at a standardised time correlated with the increased VT. Mechanical factors play an important role in shaping the ventilatory response to exercise in chronic obstructive pulmonary disease. Bronchodilator-induced lung deflation reduced mechanical restriction, increased ventilatory capacity and decreased respiratory discomfort, thereby increasing exercise endurance.
Chronic obstructive pulmonary disease (COPD) and obesity are common and disabling chronic health conditions with increasing prevalence worldwide. A relationship between COPD and obesity is ...increasingly recognised, although the nature of this association remains unknown. This review focuses on the epidemiology of obesity in COPD and the impact of excessive fat mass on lung function, exercise capacity and prognosis. The evidence for altered adipose tissue functions in obesity--including reduced lipid storage capacity, altered expression and secretion of inflammatory factors, adipose tissue hypoxia and macrophage infiltration in adipose tissue--is also reviewed. The interrelationship between these factors and their contribution to the development of insulin resistance in obesity is considered. It is proposed that, in patients with COPD, reduced oxidative capacity and systemic hypoxia may amplify these disturbances, not only in obese patients but also in subjects with hidden loss of fat-free mass. The potential interaction between abnormal adipose tissue function, systemic inflammation and COPD may provide more insight into the pathogenesis and reversibility of systemic pathology in this disease.
Evidence-based recommendations on the clinical use of cardiopulmonary exercise testing (CPET) in lung and heart disease are presented, with reference to the assessment of exercise intolerance, ...prognostic assessment and the evaluation of therapeutic interventions (e.g. drugs, supplemental oxygen, exercise training). A commonly used grading system for recommendations in evidence-based guidelines was applied, with the grade of recommendation ranging from A, the highest, to D, the lowest. For symptom-limited incremental exercise, CPET indices, such as peak O(2) uptake (V'O(2)), V'O(2) at lactate threshold, the slope of the ventilation-CO(2) output relationship and the presence of arterial O(2) desaturation, have all been shown to have power in prognostic evaluation. In addition, for assessment of interventions, the tolerable duration of symptom-limited high-intensity constant-load exercise often provides greater sensitivity to discriminate change than the classical incremental test. Field-testing paradigms (e.g. timed and shuttle walking tests) also prove valuable. In turn, these considerations allow the resolution of practical questions that often confront the clinician, such as: 1) "When should an evaluation of exercise intolerance be sought?"; 2) "Which particular form of test should be asked for?"; and 3) "What cluster of variables should be selected when evaluating prognosis for a particular disease or the effect of a particular intervention?"
Ultrasound guidance facilitates precise needle and injectate placement, increasing axillary block success rates, reducing onset times, and permitting local anesthetic dose reduction. The minimum ...effective volume of local anesthetic in ultrasound-guided axillary brachial plexus block is unknown. The authors performed a study to estimate the minimum effective anesthetic volume of 2% lidocaine with 1:200,000 epinephrine (2% LidoEpi) in ultrasound-guided axillary brachial plexus block.
After ethical approval and informed consent, patients undergoing hand surgery of less than 90 min duration were recruited. A step-up/step-down study model was used with nonprobability sequential dosing based on the outcome of the previous patient. The starting dose of 2% LidoEpi was 4 ml per nerve. Block failure resulted in a dose increase of 0.5 ml; block success in a reduction of 0.5 ml.A blinded assistant assessed sensory and motor blockade at 5-min intervals up to 30 min. Block performance time and duration were measured. Two predetermined stopping points were used; a minimum of five consecutive block success/failures and five consecutive successful blocks at 1 ml per nerve.
The study was terminated when five consecutive patients had successful blocks using 1 ml of 2% LidoEpi per nerve (overall group n = 11). All five patients had surgical anesthesia within 10 min. The mean (SD) block performance time was 445 (100) s, and block duration was 190 min (range 120-310 min). All surgical procedures were performed under regional anesthesia with anxiolytic sedation provided in 3 of 11 cases.
Successful ultrasound-guided axillary brachial plexus block may be performed with 1 ml per nerve of 2% LidoEpi.
Ventilatory inefficiency during exercise is a key pathophysiological feature of chronic obstructive pulmonary disease. Currently, it is unknown how this physiological marker relates to clinically ...relevant outcomes as resting ventilatory impairment progresses across disease stages. Slope and intercept of the linear region of the ventilation-carbon dioxide output relationship and the ratio between these variables, at the lowest point (nadir), were contrasted in 316 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-4 (forced expiratory volume in 1 s, ranging from 148% pred to 12% pred) and 69 aged- and gender-matched controls, Compared to controls, slope and intercept were higher in GOLD stages 1 and 2, leading to higher nadirs (p<0.05). Despite even larger intercepts in GOLD stages 3 and 4, slopes diminished as disease evolved (from mean±sd 35±6 in GOLD stage 1 to 24±5 in GOLD stage 3, p<0.05). As a result, there were no significant differences in nadirs among patient groups. Higher intercepts, across all stages (p<0.01), and to a lesser extent lower slopes in GOLD stages 2-4 (p<0.05), were related to greater mechanical constraints, worsening pulmonary gas exchange, higher dyspnoea scores, and poorer exercise capacity. Increases in the ventilation intercept best indicate the progression of exercise ventilatory inefficiency across the whole spectrum of chronic obstructive pulmonary disease severity.
MicroRNAs (miRNA) represent a novel class of genes that function as negative regulators of gene expression. Recently, miRNAs have been implicated in several cancers. However, aberrant miRNA ...expression and its clinicopathologic significance in human ovarian cancer have not been well documented. Here, we show that several miRNAs are altered in human ovarian cancer, with the most significantly deregulated miRNAs being miR-214, miR-199a*, miR-200a, miR-100, miR-125b, and let-7 cluster. Further, we show the frequent deregulation of miR-214, miR-199a*, miR-200a, and miR-100 in ovarian cancers. Significantly, miR-214 induces cell survival and cisplatin resistance through targeting the 3'-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3'-UTR largely abrogates miR-214-induced cell survival. These findings indicate that deregulation of miRNAs is a recurrent event in human ovarian cancer and that miR-214 induces cell survival and cisplatin resistance primarily through targeting the PTEN/Akt pathway.
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