Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Patients and methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m, followed by 250 mg/m2 weekly thereafter). Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone. © 2007 European Society for Medical Oncology.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

The Tarim picrite-basalt-rhyolite suite, a Permian flood basalt from Northwest China with contrasting rhyolites produced by fractional crystallization and anatexis

We report major and trace element composition, Sr–Nd isotopic and seismological data for a picrite–basalt–rhyolite suite from the northern Tarim uplift (NTU), northwest China. The samples were recovered from 13 boreholes at depths between 5,166 and 6,333 m. The picritic samples have high MgO (14.5–16.8 wt%, volatiles included) enriched in incompatible element and have high 87Sr/86Sr and low 143Nd/144Nd isotopic ratios (εNd (t) = −5.3; Sri = 0.707), resembling the Karoo high-Ti picrites. All the basaltic samples are enriched in TiO2 (2.1–3.2 wt%, volatiles free), have high FeOt abundances (11.27–15.75 wt%, volatiles free), are enriched in incompatible elements and have high Sr and low Nd isotopic ratios (Sri = 0.7049–0.7065; εNd (t) = −4.1 to −0.4). High Nb/La ratios (0.91–1.34) of basalts attest that they are mantle-derived magma with negligible crustal contamination. The rhyolite samples can be subdivided into two coeval groups with overlapping U–Pb zircon ages between 291 ± 4 and 272 ± 2 Ma. Group 1 rhyolites are enriched in Nb and Ta, have similar Nb/La, Nb/U, and Sr–Nd isotopic compositions to the associated basalts, implying that they are formed by fractional crystallization of the basalts. Group 2 rhyolites are depleted in Nb and Ta, have low Nb/La ratios, and have very high Sr and low Nd isotopic ratios, implying that crustal materials have been extensively, if not exclusively, involved in their source. The picrite–basalt–rhyolite suite from the NTU, together with Permian volcanic rocks from elsewhere Tarim basin, constitute a Large Igneous Province (LIP) that is characterized by large areal extent, rapid eruption, OIB-type chemical composition, and eruption of high temperature picritic magma. The Early Permian magmatism, which covered an area >300,000 km2, is therefore named the Tarim Flood Basalt.

Shadow boxing with an imaginary enemy : a response to "Law and Order Blues"

In our rejoinder to Don Weatherburn's paper,"Law and Order Blues", we do not take issue with his advocacy of the need to take crime seriously and to foster a more rational approach to the problems it poses. Where differences do emerge is (1) with his claim that he is willing to do so whilst we (in our different ways) are not; and (2) on the question of what this involves. Of particular concern is the way in which his argument proceeds by a combination of simple misrepresentation of the positions it seeks to disparage, and silence concerning issues of real substance where intellectual debate and exchange would be welcome and useful. Our paper challenges, in turn, the misrepresentation of Indermaur's analysis of trends in violent crime, the misrepresentation of Hogg and Brown's Rethinking Law and Order, the misrepresentation of the findings of some of the research into the effectiveness of punitive policies and the silence on sexual assault in "Law and Order Blues". We suggest that his silence on sexual assault reflects a more widespread unwillingness to acknowledge the methodological problems that arise in the measurement of crime because such problems severely limit the extent to which confident assertions can be made about prevalence and trends.

Theatre-arts pedagogy for social justice : case study of the area youth foundation in Jamaica

In this paper I describe and analyse the socio-educational significance of a theatre arts approach to learning for young adults in Jamaica, implemented by the Area Youth Foundation (AYF). Briefly outlining the genesis and development of the AYF, I provide snapshots of the experiences and destinations of some of its young participants. The paper discusses AYF workshops to show how the pedagogy was shaped by the expressive arts and based on the critical praxis approach systematized by Paulo Freire in adult education and Augusto Boal in theatre. Based on interviews with AYF’s leader and some of the learners, I discuss how the foundation’s motto, “Youth Empowerment Through the Arts,” is played out in workshops and creative productions that are simultaneously learner-driven and teacher-guided, with the powerful impact of inspiring politically thoughtful creativity and skills in youths from less-privileged communities.

Traffic state estimation from partial Bluetooth and volume observations : case study in the Brisbane metropolitan area

The application of the Bluetooth (BT) technology to transportation has been enabling researchers to make accurate travel time observations, in freeway and arterial roads. The Bluetooth traffic data are generally incomplete, for they only relate to those vehicles that are equipped with Bluetooth devices, and that are detected by the Bluetooth sensors of the road network. The fraction of detected vehicles versus the total number of transiting vehicles is often referred to as Bluetooth Penetration Rate (BTPR). The aim of this study is to precisely define the spatio-temporal relationship between the quantities that become available through the partial, noisy BT observations; and the hidden variables that describe the actual dynamics of vehicular traffic. To do so, we propose to incorporate a multi- class traffic model into a Sequential Montecarlo Estimation algorithm. Our framework has been applied for the empirical travel time investigations into the Brisbane Metropolitan region.

Sex-specific compromised bone healing in female rats might be associated with a decrease in mesenchymal stem cell quantity

Introduction The clinically known importance of patient sex as a major risk factor for compromised bone healing is poorly reflected in animal models. Consequently, the underlying cellular mechanisms remain elusive. Because mesenchymal stem cells (MSCs) are postulated to regulate tissue regeneration and give rise to essential differentiated cell types, they may contribute to sex-specific differences in bone healing outcomes. Methods We investigated sex-specific variations in bone healing and associated differences in MSC populations. A 1.5 mm osteotomy gap in the femora of 8 male and 8 female 12-month-old Sprague-Dawley rats was stabilized by an external fixator. Healing was analyzed in terms of biomechanical testing, bridging and callus size over time (radiography at 2, 4, and 6 weeks after surgery), and callus volume and geometry by μCT at final follow-up. MSCs were obtained from bone marrow samples of an age-matched group of 12 animals (6 per gender) and analyzed for numbers of colony-forming units (CFUs) and their capacity to differentiate and proliferate. The proportion of senescent cells was determined by β-galactosidase staining. Results Sex-specific differences were indicated by a compromised mechanical competence of the callus in females compared with males (maximum torque at failure, p = 0.028). Throughout the follow-up, the cross-sectional area of callus relative to bone was reduced in females (p ≤ 0.01), and the bridging of callus was delayed (p 2weeks = 0.041). μCT revealed a reduced callus size (p = 0.003), mineralization (p = 0.003) and polar moment of inertia (p = 0.003) in female animals. The female bone marrow contained significantly fewer MSCs, represented by low CFU numbers in both femora and tibiae (p femur = 0.017, p tibia = 0.010). Functional characteristics of male and female MSCs were similar. Conclusion Biomechanically compromised and radiographically delayed bone formation were distinctive in female rats. These differences were concomitant with a reduced number of MSCs, which may be causative for the suboptimal bone healing.

Plasmodium vivax malaria incidence over time and its association with temperature and rainfall in four counties of Yunnan Province, China

Background Transmission of Plasmodium vivax malaria is dependent on vector availability, biting rates and parasite development. In turn, each of these is influenced by climatic conditions. Correlations have previously been detected between seasonal rainfall, temperature and malaria incidence patterns in various settings. An understanding of seasonal patterns of malaria, and their weather drivers, can provide vital information for control and elimination activities. This research aimed to describe temporal patterns in malaria, rainfall and temperature, and to examine the relationships between these variables within four counties of Yunnan Province, China. Methods Plasmodium vivax malaria surveillance data (1991–2006), and average monthly temperature and rainfall were acquired. Seasonal trend decomposition was used to examine secular trends and seasonal patterns in malaria. Distributed lag non-linear models were used to estimate the weather drivers of malaria seasonality, including the lag periods between weather conditions and malaria incidence. Results There was a declining trend in malaria incidence in all four counties. Increasing temperature resulted in increased malaria risk in all four areas and increasing rainfall resulted in increased malaria risk in one area and decreased malaria risk in one area. The lag times for these associations varied between areas. Conclusions The differences detected between the four counties highlight the need for local understanding of seasonal patterns of malaria and its climatic drivers.

Environmental factors associated with active living in retirement village residents : findings from an exploratory qualitative enquiry

This exploratory enquiry employs qualitative methods to advance knowledge and understanding of physical environmental attributes related to active living among residents of Australian retirement villages. Six focus groups (n = 51 residents) were held and participants described how their current, and subsequently ideal, retirement village and neighborhood supported active lifestyles. Thematic analysis revealed three key environmental factors associated with active living: a positive social environment within the village; services and facilities provided in the village and wider neighborhood; and the presence of suitable pedestrian infrastructure. The unique discovery that environmental factors of both the retirement village and the surrounding neighborhood were associated with residents’ active living raises many questions for study. Findings informed the development of a survey instrument, and further understanding in this area has the potential to contribute to the design and siting practices of senior housing complexes within neighborhoods.

A porcine deep dermal partial thickness burn model with hypertrophic scarring

We developed a reproducible model of deep dermal partial thickness burn injury in juvenile Large White pigs. The contact burn is created using water at 92 degrees C for 15s in a bottle with the bottom replaced with plastic wrap. The depth of injury was determined by a histopathologist who examined tissue sections 2 and 6 days after injury in a blinded manner. Upon creation, the circular wound area developed white eschar and a hyperaemic zone around the wound border. Animals were kept for 6 weeks or 99 days to examine the wound healing process. The wounds took between 3 and 5 weeks for complete re-epithelialisation. Most wounds developed contracted, purple, hypertrophic scars. On measurement, the thickness of the burned skin was approximately 1.8 times that of the control skin at week 6 and approximately 2.2 times thicker than control skin at 99 days after injury. We have developed various methods to assess healing wounds, including digital photographic analysis, depth of organising granulation tissue, immunohistochemistry, electron microscopy and tensiometry. Immunohistochemistry and electron microscopy showed that our porcine hypertrophic scar appears similar to human hypertrophic scarring. The development of this model allows us to test and compare different treatments on burn wounds.

Vascular remodeling in the internal mammary artery graft and association with in situ endothelin-1 and receptor expression

BACKGROUND: The vasoconstricting peptide endothelin-1 (ET-1) has been associated with atherosclerotic cardiovascular disease, vascular smooth muscle cell (VSMC) growth stimulation, and intimal thickening. ET-1 binds 2 receptor subtypes, endothelin A and B, and the ETA receptor mediates vasoconstriction and VSMC growth. This study aims to quantitatively assess arterial remodeling variables and compare them with changes in ET-1, ETA, and ETB expression in the internal mammary artery (IMA). METHODS AND RESULTS: Specimens from 55 coronary artery disease (CAD) patients (45 men, 10 women; mean age 65 years) and 14 control IMA specimens (from 7 men and 7 women; mean age 45 years) were collected. IMA cross sections were assessed by histochemical and immunohistochemical staining methods to quantify the levels of medionecrosis, fibrosis, VSMC growth, ET-1, ETA, ETB, and macrophage infiltration. The percentage area of medionecrosis in the patients was almost double that in the controls (31.85+/-14.52% versus 17.10+/-9.96%, P=0.0006). Total and type 1 collagen was significantly increased compared with controls (65.8+/-18.3% versus 33.7+/-13.7%, P=0.07, and 14.2+/-10.0% versus 4.8+/-2.8%, P=0.01, respectively). Despite ACE and/or statin therapy, ET-1 expression and cell cycling were significantly elevated in the patient IMAs relative to the controls (46.27+/-18.46 versus 8.56+/-8.42, P=0.0001, and 37.29+/-12.88 versus 11.06+/-8.18, P=0.0001, respectively). ETA and ETB staining was elevated in the patient vessels (46.88+/-11.52% versus 18.58+/-7.65%, P=0.0001, and 42.98+/-7.08% versus 34.73+/-5.20%, P=0.0067, respectively). A mild presence of macrophages was noted in all sections. CONCLUSIONS: Elevated distribution of collagen indicative of fibrosis coupled with increased cell cycling and high levels of ET-1 and ETA expression in the absence of chronic inflammation suggests altered IMA VSMC regulation is fundamental to the remodeling process.

A comparative analysis of risk stratification tools for emergency department patients with chest pain

Background: Appropriate disposition of emergency department (ED) patients with chest pain is dependent on clinical evaluation of risk. A number of chest pain risk stratification tools have been proposed. The aim of this study was to compare the predictive performance for major adverse cardiac events (MACE) using risk assessment tools from the National Heart Foundation of Australia (HFA), the Goldman risk score and the Thrombolysis in Myocardial Infarction risk score (TIMI RS). Methods: This prospective observational study evaluated ED patients aged ≥30 years with non-traumatic chest pain for which no definitive non-ischemic cause was found. Data collected included demographic and clinical information, investigation findings and occurrence of MACE by 30 days. The outcome of interest was the comparative predictive performance of the risk tools for MACE at 30 days, as analyzed by receiver operator curves (ROC). Results: Two hundred eighty-one patients were studied; the rate of MACE was 14.1%. Area under the curve (AUC) of the HFA, TIMI RS and Goldman tools for the endpoint of MACE was 0.54, 0.71 and 0.67, respectively, with the difference between the tools in predictive ability for MACE being highly significant [chi2 (3) = 67.21, N = 276, p < 0.0001]. Conclusion: The TIMI RS and Goldman tools performed better than the HFA in this undifferentiated ED chest pain population, but selection of cutoffs balancing sensitivity and specificity was problematic. There is an urgent need for validated risk stratification tools specific for the ED chest pain population.

Standardising corneal nerve fibre length for nerve tortuosity increases its association with measures of diabetic neuropathy

AIMS: Recent studies on corneal markers have advocated corneal nerve fibre length as the most important measure of diabetic peripheral neuropathy. The aim of this study was to determine if standardizing corneal nerve fibre length for tortuosity increases its association with other measures of diabetic peripheral neuropathy. METHODS: Two hundred and thirty-one individuals with diabetes with either predominantly mild or absent neuropathic changes and 61 control subjects underwent evaluation of diabetic neuropathy symptom score, neuropathy disability score, testing with 10-g monofilament, quantitative sensory testing (warm, cold, vibration detection) and nerve conduction studies. Corneal nerve fibre length and corneal nerve fibre tortuosity were measured using corneal confocal microscopy. A tortuosity-standardised corneal nerve fibre length variable was generated by dividing corneal nerve fibre length by corneal nerve fibre tortuosity. Differences in corneal nerve morphology between individuals with and without diabetic peripheral neuropathy and control subjects were determined and associations were estimated between corneal morphology and established tests of, and risk factors for, diabetic peripheral neuropathy. RESULTS: The tortuosity-standardised corneal nerve fibre length variable was better than corneal nerve fibre length in demonstrating differences between individuals with diabetes, with and without neuropathy (tortuosity-standardised corneal nerve fibre length variable: 70.5 ± 27.3 vs. 84.9 ± 28.7, P < 0.001, receiver operating characteristic area under the curve = 0.67; corneal nerve fibre length: 15.9 ± 6.9 vs. 18.4 ± 6.2 mm/mm(2) , P = 0.004, receiver operating characteristic area under the curve = 0.64). Furthermore, the tortuosity-standardised corneal nerve fibre length variable demonstrated a significant difference between the control subjects and individuals with diabetes, without neuropathy, while corneal nerve fibre length did not (tortuosity-standardised corneal nerve fibre length variable: 94.3 ± 27.1 vs. 84.9 ± 28.7, P = 0.028; corneal nerve fibre length: 20.1 ± 6.3 vs. 18.4 ± 6.2 mm/mm(2) , P = 0.084). Correlations between corneal nerve fibre length and established measures of neuropathy and risk factors for neuropathy were higher when a correction was made for the nerve tortuosity. CONCLUSIONS: Standardizing corneal nerve fibre length for tortuosity enhances the ability to differentiate individuals with diabetes, with and without neuropathy.

Associations between area-level disadvantage and DMFT among a birth cohort of Indigenous Australians

Background Individual-level factors influence DMFT, but little is known about the influence of community environment. This study examines associations between community-level influences and DMFT among a birth cohort of Indigenous Australians aged 16–20 years. Methods Data were collected as part of Wave 3 of the Aboriginal Birth Cohort study. Fifteen community areas were established and the sample comprised 442 individuals. The outcome variable was mean DMFT with explanatory variables including diet and community disadvantage (access to services, infrastructure and communications). Data were analysed using multilevel regression modelling. Results In a null model, 13.8% of the total variance in mean DMFT was between community areas, which increased to 14.3% after adjusting for sex, age and diet. Addition of the community disadvantage variable decreased the variance between areas by 4.8%, indicating that community disadvantage explained one-third of the area-level variance. Residents of under-resourced communities had significantly higher mean DMFT (β=3.86, 95% CI 0.02¬, 7.70) after adjusting for sex, age and diet. Conclusions Living in under-resourced communities was associated with greater DMFT among this disadvantaged population, indicating that policies aiming to reduce oral health-related inequalities among vulnerable groups may benefit from taking into account factors external to individual-level influences.