Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2 : prognostic factors and treatment selection based on two large randomized clinical trials

Purpose: Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2. Patients and Methods: Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy. Results: Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival imes were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin <3.5 g, extrathoracic metastases, lactate dehydrogenase ≥200 IU, and 2 comorbid conditions predicted outcome. Patients with 0-2 risk factors had similar outcomes independent of treatment, whereas patients with 3-4 factors had a nonsignificant improvement in median survival with combination chemotherapy. Conclusion: Our results show that PS2 non-small cell lung cancer patients are a heterogeneous group who have significantly different outcomes. Patients treated with first-line combination chemotherapy had a higher response and longer time to progression, whereas overall survival did not appear significantly different. A prognostic model may be helpful in selecting PS 2 patients for either treatment strategy. © 2009 by the International Association for the Study of Lung Cancer.

The Arabidopsis thaliana double-stranded RNA binding protein DRB1 directs guide strand selection from microRNA duplexes

In Arabidopsis thaliana (Arabidopsis), DICER-LIKE1 (DCL1) functions together with the double-stranded RNA binding protein (dsRBP), DRB1, to process microRNAs (miRNAs) from their precursor transcripts prior to their transfer to the RNA-induced silencing complex (RISC). miRNA-loaded RISC directs RNA silencing of cognate mRNAs via ARGONAUTE1 (AGO1)-catalyzed cleavage. Short interefering RNAs (siRNAs) are processed from viral-derived or transgene-encoded molecules of doublestranded RNA (dsRNA) by the DCL/dsRBP partnership, DCL4/DRB4, and are also loaded to AGO1-catalyzed RISC for cleavage of complementary mRNAs. Here, we use an artificial miRNA (amiRNA) technology, transiently expressed in Nicotiana benthamiana, to produce a series of amiRNA duplexes with differing intermolecular thermostabilities at the 5′ end of duplex strands. Analyses of amiRNA duplex strand accumulation and target transcript expression revealed that strand selection (amiRNA and amiRNA*) is directed by asymmetric thermostability of the duplex termini. The duplex strand possessing a lower 59 thermostability was preferentially retained by RISC to guide mRNA cleavage of the corresponding target transgene. In addition, analysis of endogenous miRNA duplex strand accumulation in Arabidopsis drb1 and drb2345 mutant plants revealed that DRB1 dictates strand selection, presumably by directional loading of the miRNA duplex onto RISC for passenger strand degradation. Bioinformatic and Northern blot analyses of DCL4/DRB4-dependent small RNAs (miRNAs and siRNAs) revealed that small RNAs produced by this DCL/dsRBP combination do not conform to the same terminal thermostability rules as those governing DCL1/DRB1-processed miRNAs. This suggests that small RNA processing in the DCL1/DRB1-directed miRNA and DCL4/DRB4-directed sRNA biogenesis pathways operates via different mechanisms.

A novel T-DNA vector design for selection of transgenic lines with simple transgene integration and stable transgene expression

Plants transformed with Agrobacterium frequently contain T-DNA concatamers with direct-repeat (d/r) or inverted-repeat (i/r) transgene integrations, and these repetitive T-DNA insertions are often associated with transgene silencing. To facilitate the selection of transgenic lines with simple T-DNA insertions, we constructed a binary vector (pSIV) based on the principle of hairpin RNA (hpRNA)-induced gene silencing. The vector is designed so that any transformed cells that contain more than one insertion per locus should generate hpRNA against the selective marker gene, leading to its silencing. These cells should, therefore, be sensitive to the selective agent and less likely to regenerate. Results from Arabidopsis and tobacco transformation showed that pSIV gave considerably fewer transgenic lines with repetitive insertions than did a conventional T-DNA vector (pCON). Furthermore, the transgene was more stably expressed in the pSIV plants than in the pCON plants. Rescue of plant DNA flanking sequences from pSIV plants was significantly more frequent than from pCON plants, suggesting that pSIV is potentially useful for T-DNA tagging. Our results revealed a perfect correlation between the presence of tail-to-tail inverted repeats and transgene silencing, supporting the view that read-through hpRNA transcript derived from i/r T-DNA insertions is a primary inducer of transgene silencing in plants. © CSIRO 2005.

Biomechanical characteristics of peripheral diabetic neuropathy : a systematic review and meta-analysis of findings from the gait cycle, muscle activity and dynamic barefoot plantar pressure

Background: Diabetic peripheral neuropathy is an important cause of foot ulceration and limb loss. This systematic review and meta-analysis investigated the effect of diabetic peripheral neuropathy on gait, dynamic electromyography and dynamic plantar pressures. Methods: Electronic databases were searched systematically for articles reporting the effect of diabetic peripheral neuropathy on gait, dynamic electromyography and plantar pressures. Searches were restricted to articles published between January 2000 and April 2012. Outcome measures assessed included spatiotemporal parameters, lower limb kinematics, kinetics, muscle activation and plantar pressure. Meta-analyses were carried out on all outcome measures reported by ≥3 studies. Findings: Sixteen studies were included consisting of 382 neuropathy participants, 216 diabetes controls without neuropathy and 207 healthy controls. Meta-analysis was performed on 11 gait variables. A high level of heterogeneity was noted between studies. Meta-analysis results suggested a longer stance time and moderately higher plantar pressures in diabetic peripheral neuropathy patients at the rearfoot, midfoot and forefoot compared to controls. Systematic review of studies suggested potential differences in the biomechanical characteristics (kinematics, kinetics, EMG) of diabetic neuropathy patients. However these findings were inconsistent and limited by small sample sizes.; Interpretation: Current evidence suggests that patients with diabetic peripheral neuropathy have elevated plantar pressures and occupy a longer duration of time in the stance-phase during gait. Firm conclusions are hampered by the heterogeneity and small sample sizes of available studies. Interpretation: Current evidence suggests that patients with diabetic peripheral neuropathy have elevated plantar pressures and occupy a longer duration of time in the stance-phase during gait. Firm conclusions are hampered by the heterogeneity and small sample sizes of available studies.

Quality based frame selection for face clustering in news video

Clustering identities in a broadcast video is a useful task to aid in video annotation and retrieval. Quality based frame selection is a crucial task in video face clustering, to both improve the clustering performance and reduce the computational cost. We present a frame work that selects the highest quality frames available in a video to cluster the face. This frame selection technique is based on low level and high level features (face symmetry, sharpness, contrast and brightness) to select the highest quality facial images available in a face sequence for clustering. We also consider the temporal distribution of the faces to ensure that selected faces are taken at times distributed throughout the sequence. Normalized feature scores are fused and frames with high quality scores are used in a Local Gabor Binary Pattern Histogram Sequence based face clustering system. We present a news video database to evaluate the clustering system performance. Experiments on the newly created news database show that the proposed method selects the best quality face images in the video sequence, resulting in improved clustering performance.

Ureaplasma parvum undergoes selection in utero resulting in genetically diverse isolates colonising the chorioamnion of fetal sheep

Ureaplasmas are the microorganisms most frequently isolated from the amniotic fluid of pregnant women and can cause chronic intrauterine infections. These tiny bacteria are thought to undergo rapid evolution and exhibit a hypermutatable phenotype; however, little is known about how ureaplasmas respond to selective pressures in utero. Using an ovine model of chronic intra-amniotic infection, we investigated if exposure of ureaplasmas to sub-inhibitory concentrations of erythromycin could induce phenotypic or genetic indicators of macrolide resistance. At 55 days gestation, 12 pregnant ewes received an intra-amniotic injection of a non-clonal, clinical U. parvum strain, followed by: (i) erythromycin treatment (IM, 30 mg/kg/day, n=6); or (ii) saline (IM, n=6) at 100 days gestation. Fetuses were then delivered surgically at 125 days gestation. Despite injecting the same inoculum into all ewes, significant differences between amniotic fluid and chorioamnion ureaplasmas were detected following chronic intra-amniotic infection. Numerous polymorphisms were observed in domain V of the 23S rRNA gene of ureaplasmas isolated from the chorioamnion (but not the amniotic fluid), resulting in a mosaic-like sequence. Chorioamnion isolates also harboured the macrolide resistance genes erm(B) and msr(D) and were associated with variable roxithromycin minimum inhibitory concentrations. Remarkably, this variability occurred independently of exposure of ureaplasmas to erythromycin, suggesting that low-level erythromycin exposure does not induce ureaplasmal macrolide resistance in utero. Rather, the significant differences observed between amniotic fluid and chorioamnion ureaplasmas suggest that different anatomical sites may select for ureaplasma sub-types within non-clonal, clinical strains. This may have implications for the treatment of intrauterine ureaplasma infections.

Portfolio selection using artificial intelligence

The application of artificial intelligence in finance is relatively new area of research. This project employed artificial neural networks (ANNs) that use both fundamental and technical inputs to predict future prices of widely held Australian stocks and use these predicted prices for stock portfolio selection over a long investment horizon. The research involved the creation and testing of a large number of possible network configurations and draws conclusions about ANN architectures and their overall suitability for the purpose of stock portfolio selection.

Continuous positive air pressure treatment for obstructive sleep apnoea patients : effects on sleep quality and quantity as measured by actigraphy

Objectives Actigraphy can reliably assess sleep in healthy adults and be used to estimate total sleep time in suspected obstructive sleep apnoea (OSA) patients. We compared sleep quality for Continuous Positive Air Pressure (CPAP) treated OSA patients and controls, evaluating the impact of stopping CPAP for one night. Methods 11 men, aged 51–75 years (m = 65.6 years), compliant CPAP users, treated for 1–19 years (m = 7.8 years) wore Cambridge Neurotechnology Ltd actiwatches for one night while using CPAP and for one night sleeping without CPAP. A control group of 11 healthy men, aged 63–74 years (m = 64.1 years) slept normally whilst wearing an actiwatch. Subsequent daytime sleepiness was recorded using Karolinska sleepiness scores (KSS). Results Actimetry showed no significant differences between actual sleep time, sleep efficiency, sleep disturbance index or number of wake bouts when comparing OSA participants using CPAP, with controls; there was no difference in subsequent daytime sleepiness, control KSS = 4.21, OSA KSS = 4.17. Without CPAP there was no significant difference in sleep length or sleep onset latency compared with using CPAP, but there was a significant impact on sleep quality as shown by: increased sleep disturbance index from 7.9 to 13.8 [t(10) = 3.510, P < 0.05], decreased percent of actual sleep from 92.05% to 86.15% [t(10) = 3.51, P < 0.05], decreased sleep efficiency from 86.6% to 81% [t(10) = 2.204, P < 0.05] and increased number of wake bouts from 29 to 42.5 [t(10) = 3.877, P < 0.05]. Daytime sleepiness became significantly worse increasing from KSS 4.17 to 6.27 [t(10) = )4.96, P < 0.05]. Conclusion There was no disparity in sleep quality or KSS scores between CPAP treated OSA patients and healthy controls of a similar age. Treated OSA patients obtained quality sleep with no elevated day time sleepiness. However, cessation of treatment for one night caused sleep quality to deteriorate despite a comparable sleep time; the deterioration in sleep quality could explain the increase in daytime sleepiness. OSA patients need to know that even short-term noncompliance with CPAP treatment significantly impairs sleep quality, leading to excessive sleepiness during monotonous tasks such as driving. Actigraphy successfully identified nights of non-compliance in treated OSA patients; but did not differentiate between the sleep of CPAP treated OSA patients and healthy controls.

Selling new neighborhoods as good for walking : issues for measuring self-selection

Background: Self-selection-whether individuals inclined to walk more seek to live in walkable environments-must be accounted for when studying built environment influences on walking. The way neighborhoods are marketed to future residents has the potential to sway residential location choice, and may consequently affect measures of self-selection related to location preferences. We assessed how walking opportunities are promoted to potential buyers, by examining walkability attributes in marketing materials for housing developments. Methods: A content analysis of marketing materials for 32 new housing developments in Perth, Australia was undertaken, to assess how walking was promoted in the text and pictures. Housing developments designed to be pedestrian-friendly (LDs) were compared with conventional developments (CDs). Results: Compared with CDs, LD marketing materials had significantly more references to 'public transport,' small home sites,' walkable parks/open space,' ease of cycling,' safe environment,' and 'boardwalks.' Other walkability attributes approached significance. Conclusion: Findings suggest the way neighborhoods are marketed may contribute to self-reported reasons for choosing particular neighborhoods, especially when attributes are not present at the time of purchase. The marketing of housing developments may be an important factor to consider when measuring self-selection, and its influence on the built environment and walking relationship.

Selection and monitoring of navigation modes for an autonomous rover

Considering the wide spectrum of situations that it may encounter, a robot navigating autonomously in outdoor environments needs to be endowed with several operating modes, for robustness and efficiency reasons. Indeed, the terrain it has to traverse may be composed of flat or rough areas, low cohesive soils such as sand dunes, concrete road etc... Traversing these various kinds of environment calls for different navigation and/or locomotion functionalities, especially if the robot is endowed with different locomotion abilities, such as the robots WorkPartner, Hylos [4], Nomad or the Marsokhod rovers.

Selection and monitoring of navigation modes for an autonomous rover

Considering the wide spectrum of situations that it may encounter, a robot navigating autonomously in outdoor environments needs to be endowed with several operating modes, for robustness and efficiency reasons. Indeed, the terrain it has to traverse may be composed of flat or rough areas, low cohesive soils such as sand dunes, concrete road etc. . .Traversing these various kinds of environment calls for different navigation and/or locomotion functionalities, especially if the robot is endowed with different locomotion abilities, such as the robots WorkPartner, Hylos [4], Nomad or the Marsokhod rovers. Numerous rover navigation techniques have been proposed, each of them being suited to a particular environment context (e.g. path following, obstacle avoidance in more or less cluttered environments, rough terrain traverses...). However, seldom contributions in the literature tackle the problem of selecting autonomously the most suited mode [3]. Most of the existing work is indeed devoted to the passive analysis of a single navigation mode, as in [2]. Fault detection is of course essential: one can imagine that a proper monitoring of the Mars Exploration Rover Opportunity could have avoided the rover to be stuck during several weeks in a dune, by detecting non-nominal behavior of some parameters. But the ability to recover the anticipated problem by switching to a better suited navigation mode would bring higher autonomy abilities, and therefore a better overall efficiency. We propose here a probabilistic framework to achieve this, which fuses environment related and robot related information in order to actively control the rover operations.

Selection et controle de modes de deplacement pour un robot mobile autonome en environnements naturels

Autonomous navigation and locomotion of a mobile robot in natural environments remain a rather open issue. Several functionalities are required to complete the usual perception/decision/action cycle. They can be divided in two main categories : navigation (perception and decision about the movement) and locomotion (movement execution). In order to be able to face the large range of possible situations in natural environments, it is essential to make use of various kinds of complementary functionalities, defining various navigation and locomotion modes. Indeed, a number of navigation and locomotion approaches have been proposed in the literature for the last years, but none can pretend being able to achieve autonomous navigation and locomotion in every situation. Thus, it seems relevant to endow an outdoor mobile robot with several complementary navigation and locomotion modes. Accordingly, the robot must also have means to select the most appropriate mode to apply. This thesis proposes the development of such a navigation/locomotion mode selection system, based on two types of data: an observation of the context to determine in what kind of situation the robot has to achieve its movement and an evaluation of the behavior of the current mode, made by monitors which influence the transitions towards other modes when the behavior of the current one is considered as non satisfying. Hence, this document introduces a probabilistic framework for the estimation of the mode to be applied, some navigation and locomotion modes used, a qualitative terrain representation method (based on the evaluation of a difficulty computed from the placement of the robot's structure on a digital elevation map), and monitors that check the behavior of the modes used (evaluation of rolling locomotion efficiency, robot's attitude and configuration watching. . .). Some experimental results obtained with those elements integrated on board two different outdoor robots are presented and discussed.

Visual analog scale and pressure pain threshold for delayed onset muscle soreness assessment

Objectives: To investigate the relationship between two assessments to quantify delayed onset muscle soreness [DOMS]: visual analog scale [VAS] and pressure pain threshold [PPT]. Methods: Thirty-one healthy young men [25.8 ± 5.5 years] performed 10 sets of six maximal eccentric contractions of the elbow flexors with their non-dominant arm. Before and one to four days after the exercise, muscle pain perceived upon palpation of the biceps brachii at three sites [5, 9 and 13 cm above the elbow crease] was assessed by VAS with a 100 mm line [0 = no pain, 100 = extremely painful], and PPT of the same sites was determined by an algometer. Changes in VAS and PPT over time were compared amongst three sites by a two-way repeated measures analysis of variance, and the relationship between VAS and PPT was analyzed using a Pearson product-moment correlation. Results: The VAS increased one to four days after exercise and peaked two days post-exercise, while the PPT decreased most one day post-exercise and remained below baseline for four days following exercise [p < 0.05]. No significant difference among the three sites was found for VAS [p = 0.62] or PPT [p = 0.45]. The magnitude of change in VAS did not significantly correlate with that of PPT [r = −0.20, p = 0.28]. Conclusion: These results suggest that the level of muscle pain is not region-specific, at least among the three sites investigated in the study, and VAS and PPT provide different information about DOMS, indicating that VAS and PPT represent different aspects of pain.

Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

Background and Purpose The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. Experimental Approach C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. Key Results (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. Conclusions and Implications β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.