ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

Background: The H69CIS200 and H69OX400 cell lines are novel models of low-level platinum-drug resistance. Resistance was not associated with increased cellular glutathione or decreased accumulation of platinum, rather the resistant cell lines have a cell cycle alteration allowing them to rapidly proliferate post drug treatment. Results: A decrease in ERCC1 protein expression and an increase in RAD51B foci activity was observed in association with the platinum induced cell cycle arrest but these changes did not correlate with resistance or altered DNA repair capacity. The H69 cells and resistant cell lines have a p53 mutation and consequently decrease expression of p21 in response to platinum drug treatment, promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. Conclusion: Decreased ERCC1 protein and increased RAD51B foci may in part be mediating the maintenance of the cell cycle arrest in the sensitive cells. Resistance in the H69CIS200 and H69OX400 cells may therefore involve the regulation of ERCC1 and RAD51B independent of their roles in DNA repair. The novel mechanism of platinum resistance in the H69CIS200 and H69OX400 cells demonstrates the multifactorial nature of platinum resistance which can occur independently of alterations in DNA repair capacity and changes in ERCC1

The association between iliocostal distance and the number of vertebral and non-vertebral fractures in women and men registered in the Canadian Database For Osteoporosis and Osteopenia (CANDOO)

BACKGROUND: The identification of new methods of evaluating patients with osteoporotic fracture should focus on their usefulness in clinical situations such that they are easily measured and applicable to all patients. Thus, the purpose of this study was to examine the association between iliocostal distance and vertebral and non-vertebral fractures in patients seen in a clinical setting. METHODS: Patient data were obtained from the Canadian Database of Osteoporosis and Osteopenia (CANDOO). A total of 549 patients including 508 women and 41 men participated in this cross-sectional study. There were 142 women and 18 men with prevalent vertebral fractures, and 185 women and 21 men with prevalent non-vertebral fractures. RESULTS: In women multivariable regression analysis showed that iliocostal distance was negatively associated with the number of vertebral fractures (-0.18, CI: -0.27, -0.09; adjusted for bone mineral density at the Ward's triangle, epilepsy, cerebrovascular disease, inflammatory bowel disease, etidronate use, and calcium supplement use) and for the number of non-vertebral fractures (-0.09, CI: -0.15, -0.03; adjusted for bone mineral density at the trochanter, cerebrovascular disease, inflammatory bowel disease, and etidronate use). However, in men, multivariable regression analysis did not demonstrate a significant association between iliocostal distance and the number of vertebral and non-vertebral fractures. CONCLUSIONS: The examination of iliocostal distance may be a useful clinical tool for assessment of the possibility of vertebral fractures. The identification of high-risk patients is important to effectively use the growing number of available osteoporosis therapies

Community based intervention to optimize osteoporosis management: randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Osteoporosis-related fractures are a significant public health concern. Interventions that increase detection and treatment of osteoporosis are underutilized. This pragmatic randomised study was done to evaluate the impact of a multifaceted community-based care program aimed at optimizing evidence-based management in patients at risk for osteoporosis and fractures.</p> <p>Methods</p> <p>This was a 12-month randomized trial performed in Ontario, Canada. Eligible patients were community-dwelling, aged ≥55 years, and identified to be at risk for osteoporosis-related fractures. Two hundred and one patients were allocated to the intervention group or to usual care. Components of the intervention were directed towards primary care physicians and patients and included facilitated bone mineral density testing, patient education and patient-specific recommendations for osteoporosis treatment. The primary outcome was the implementation of appropriate osteoporosis management.</p> <p>Results</p> <p>101 patients were allocated to intervention and 100 to control. Mean age of participants was 71.9 ± 7.2 years and 94% were women. Pharmacological treatment (alendronate, risedronate, or raloxifene) for osteoporosis was increased by 29% compared to usual care (56% [29/52] vs. 27% [16/60]; relative risk [RR] 2.09, 95% confidence interval [CI] 1.29 to 3.40). More individuals in the intervention group were taking calcium (54% [54/101] vs. 20% [20/100]; RR 2.67, 95% CI 1.74 to 4.12) and vitamin D (33% [33/101] vs. 20% [20/100]; RR 1.63, 95% CI 1.01 to 2.65).</p> <p>Conclusions</p> <p>A multi-faceted community-based intervention improved management of osteoporosis in high risk patients compared with usual care.</p> <p>Trial Registration</p> <p>This trial has been registered with clinicaltrials.gov (ID: NCT00465387)</p

Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: The risedronate and alendronate (REAL) cohort study

INTRODUCTION: Randomized clinical trials have shown that risedronate and alendronate reduce fractures among women with osteoporosis. The aim of this observational study was to observe, in clinical practice, the incidence of hip and nonvertebral fractures among women in the year following initiation of once-a-week dosing of either risedronate or alendronate. METHODS: Using records of health service utilization from July 2002 through September 2004, we created two cohorts: women (ages 65 and over) receiving risedronate (n = 12,215) or alendronate (n = 21,615). Cox proportional hazard modeling was used to compare the annual incidence of nonvertebral fractures and of hip fractures between cohorts, adjusting for potential differences in risk factors for fractures. RESULTS: There were 507 nonvertebral fractures and 109 hip fractures. Through one year of therapy, the incidence of nonvertebral fractures in the risedronate cohort (2.0%) was 18% lower (95% CI 2% – 32%) than in the alendronate cohort (2.3%). The incidence of hip fractures in the risedronate cohort (0.4%) was 43% lower (95% CI 13% – 63%) than in the alendronate cohort (0.6%). These results were consistent across a number of sensitivity analyses. CONCLUSION: Patients receiving risedronate have lower rates of hip and nonvertebral fractures during their first year of therapy than patients receiving alendronate

Transmitters and Pathways Mediating Inhibition of Spinal Itch-Signaling Neurons by Scratching and Other Counterstimuli

Scratching relieves itch, but the underlying neural mechanisms are poorly understood. We presently investigated a role for the inhibitory neurotransmitters GABA and glycine in scratch-evoked inhibition of spinal itch-signaling neurons in a mouse model of chronic dry skin itch. Superficial dorsal horn neurons ipsilateral to hindpaw dry skin treatment exhibited a high level of spontaneous firing that was significantly attenuated by cutaneous scratching, pinch and noxious heat. Scratch-evoked inhibition was nearly abolished by spinal delivery of the glycine antagonist, strychnine, and was markedly attenuated by respective GABAA and GABAB antagonists bicuculline and saclofen. Scratch-evoked inhibition was also significantly attenuated (but not abolished) by interruption of the upper cervical spinal cord, indicating the involvement of both segmental and suprasegmental circuits that engage glycine- and GABA-mediated inhibition of spinal itch-signaling neurons by noxious counterstimuli

PDEPT: polymer-directed enzyme prodrug therapy

Polymer-directed enzyme prodrug therapy (PDEPT) is a novel two-step antitumour approach using a combination of a polymeric prodrug and polymer-enzyme conjugate to generate cytotoxic drug selectively at the tumour site. In this study the polymeric prodrug N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-Gly-Phe-Leu-Gly-doxorubicin conjugate PK1 (currently under Phase II clinical evaluation) was selected as the model prodrug, and HPMA copolymer-cathepsin B as a model for the activating enzyme conjugate. Following polymer conjugation (yield of 30–35%) HPMA copolymer-cathepsin B retained ~20–25% enzymatic activity in vitro. To investigate pharmacokinetics in vivo,125I-labelled HPMA copolymer-cathepsin B was administered intravenously (i.v.) to B16F10 tumour-bearing mice. HPMA copolymer-cathespin B exhibited a longer plasma half-life (free cathepsin B t1/2α= 2.8 h; bound cathepsin B t1/2α= 3.2 h) and a 4.2-fold increase in tumour accumulation compared to the free enzyme. When PK1 (10 mg kg−1dox-equiv.) was injected i.v. into C57 mice bearing subcutaneously (s.c.) palpable B16F10 tumours followed after 5 h by HPMA copolymer-cathepsin B there was a rapid increase in the rate of dox release within the tumour (3.6-fold increase in the AUC compared to that seen for PK1 alone). When PK1 and the PDEPT combination were used to treat established B16F10 melanoma tumour (single dose; 10 mg kg−1dox-equiv.), the antitumour activity (T/C%) seen for the combination PDEPT was 168% compared to 152% seen for PK1 alone, and 144% for free dox. Also, the PDEPT combination showed activity against a COR-L23 xenograft whereas PK1 did not. PDEPT has certain advantages compared to ADEPT and GDEPT. The relatively short plasma residence time of the polymeric prodrug allows subsequent administration of polymer-enzyme without fear of prodrug activation in the circulation and polymer-enzyme conjugates have reduced immunogenicity. This study proves the concept of PDEPT and further optimisation is warranted. © 2001 Cancer Research Campaign   http://www.bjcancer.co

Association between risk factors for injurious falls and new benzodiazepine prescribing in elderly persons

<p>Abstract</p> <p>Background</p> <p>Benzodiazepines are frequently prescribed to elderly patients' despite concerns about adverse effects leading to injurious falls. Previous studies have not investigated the extent to which patients with pre-existing risk factors for falls are prescribed benzodiazepines. The objective of this study is to assess if some of the risk factors for falls are associated with new benzodiazepine prescriptions in elderly persons.</p> <p>Methods</p> <p>Using provincial administrative databases, elderly Quebec residents were screened in 1989 for benzodiazepine use and non-users were followed for up to 5 years. Logistic regression models were used to evaluate potential predictors of new benzodiazepine use among patient baseline characteristics.</p> <p>Results</p> <p>In the 252,811 elderly patients who had no benzodiazepine prescription during the baseline year (1989), 174,444 (69%) never filled a benzodiazepine prescription and 78,367 (31%) filled at least one benzodiazepine prescription. In the adjusted analysis, several risk factors for falls were associated with statistically significant increases in the risk of receiving a new benzodiazepine prescription including the number of prescribing physicians seen at baseline (OR: 1.12; 95% CI 1.11–1.13), being female (OR: 1.20; 95% CI 1.18–1.22) or a diagnosis of arthritis (OR: 1.11; 95% CI 1.09–1.14), depression (OR: 1.42; 95% CI 1.35–1.49) or alcohol abuse (OR: 1.24; 95% CI 1.05–1.46). The strongest predictor for starting a benzodiazepine was the use of other medications, particularly anti-depressants (OR: 1.85; 95% CI 1.75–1.95).</p> <p>Conclusion</p> <p>Patients with pre-existing conditions that increase the risk of injurious falls are significantly more likely to receive a new prescription for a benzodiazepine. The strength of the association between previous medication use and new benzodiazepine prescriptions highlights an important medication safety issue.</p

De jure determinants of new firm formation: how the pillars of constitutions influence entrepreneurship

This paper provides empirical evidence supporting the view that constitutions are the primary and fundamental institutional determinant of entrepreneurship. It shows that some of the provisions contained in national constitutions are positively and significantly associated with a standard measure of entrepreneurial dynamics, namely the rate of new business density. Using for 115 countries a novel dataset containing the characteristics of the constitutions enacted in the world, applying an IV-GMM treatment to deal with the endogeneity of constitutional rules, and controlling for de facto variables, the paper finds that provisions about the right to conduct/establish a business, the right to strike, consumer protection, anti-corruption, and compulsory education promote higher rates of new firm formation. Contrasting results are instead obtained for provisions concerning protection of intellectual property rights

Interstitial lung disease in children - genetic background and associated phenotypes

Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice