REDUCED CARDIOTOXICITY AND INCREASED CYTOTOXICITY IN A NOVEL ANTHRACYCLINE ANALOG, 4'-AMINO-3'-HYDROXY-DOXORUBICIN

The acute and chronic cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4'-amino-3'-hydroxy-DXR were compared with those of 4'-deoxy-DXR and DXR. In the acute cardiotoxicity study, the ECG and hemodynamic changes recorded in anesthetized rats that had been treated i.v. with 10 mg/kg 4'-amino-3'-hydroxy-DXR or 8.6 mg/kg 4'-deoxy-DXR were significantly less severe than those caused by 13 mg/kg DXR. In the chronic cardiotoxicity study, rats received 3 weekly i.v. injections of 3 mg/kg DXR, 3 mg/kg 4'-amino-3'-hydroxy-DXR, or 2 mg/kg 4'-deoxy-DXR during the first 14 days of the study and were observed for an additional 35-day period. DXR induced severe cardiomyopathy that was characterized by ECG changes in vivo (S-alpha-T-segment widening and T-wave flattening) and by impairment of the contractile responses (F(max), +/- dF/dt(max)) to adrenaline of hearts isolated from treated animals. 4'-Deoxy-DXR caused a progressive enlargement of the S-alpha-T segment in vivo and a significant impairment of the - dF/dt(max) value in vitro, which were less severe than those produced by DXR. The least cardiotoxic drug was 4'-amino-3'-hydroxy-DXR, which induced minor ECG changes without causing significant alterations in the contractile responses of isolated hearts to adrenaline. On the basis of the drug concentration required to inhibit 50% of the colony formation (IC50) of cell lines in vitro, 4'-amino-3'-hydroxy-DXR was less active than 4'-deoxy-DXR but at least twice as active as DXR against human cancer and murine transformed cell lines. These data indicate that 4'-amino-3'-hydroxy-DXR is significantly less cardiotoxic and more cytotoxic than DXR

CAN METABOLIC SYNDROME AFFECT THE EFFICACY OUTCOMES OF COMBINATION THERAPY WITH DAILY TADALAFIL 5MG PLUS TAMSULOSIN 0.4MG IN MEN WITH LUTS AND ED?

INTRODUCTION AND OBJECTIVE: Metabolic Syndrome (METS) has a high prevalence (26.5%–55.6%) in men with LUTS and erectile dysfunction (ED). Daily tadalafil 5mg intake is currently recognized as an effective pharmacological treatment for male LUTS, alone or in combination with alpha-lithics such as tamsulosin 0,4mg, ensuring a greater LUTS relieve. Aim of this study is to assess if METS could affect the efficacy of combination therapy with daily tadalafil 5mg plus tamsulosin 0,4mg in men with LUTS and ED. METHODS: Across 12 months, fifty consecutive patients aged >40 to 80 years, with moderate to severe LUTS (IPSS >7) and mild to severe ED (IIEF-5 <22) were enrolled and treated with the previous combination therapy for 12 weeks. The assessment of patients included age, body mass index (BMI), METS features - waist circumference (WC), blood pressure, clinical laboratory parameters- digital rectal examination, IPSS, OABq, uroflowmetry and postvoid residual (PVR) volume, IIEF-5. METS was defined according to NCEP ATP III. Differences were calculated by unpaired sample t-test at baseline and 12 weeks. The analysis of variance (ANOVA) was used for between-group differences. RESULTS: Among 50 patients enrolled, 31 (62.0%) had METS. Mean age was similar with 65.5 years (9.1) in patients without METS and 67.1 years (7.2) in METS patients, p=0.133. Baseline IPSS, OAB-q and IPSS QoL were significantly higher in patients with METS (p<0.05), while IIEF was higher in patients without METS (p=0.039) at baseline (Table1). After 3 months of combination therapy, IIEF, total IPSS and subscores, OAB-q and Qmax significantly improved in both groups. DeltaIPSS, deltaQMax and deltaIIEF were similar between groups (p>0.05). However, total IPSS, IPSS QoL, IPSS Voiding and IPSS Storage were significantly better at the end of the trial in men without METS. Conversely, 12wks IIEF was similar in patients with or without METS (16.3 vs 17.7 p=0.238) (Table2). CONCLUSIONS: Tadalafil plus tamsulosin combi therapy represents an effective LUTS treatment in male, independently from METS. Despite a similar improvement of LUTS (delta), patients without METS obtained a significantly better LUTS relieve. Interestingly, the efficacy in ED was greater in men with METS and, at the end of trial, IEEF-5 scores were similar in the two groups

Exploring Quaker organising to consider the possibilities for relational leadership

This paper develops the perspective of ‘relational leadership’ by exploring dynamics of influence within Quaker organising. The theory of relational leadership is drawn upon as it is connected with more sustainable and equitable ways of organising. A Quaker context is studied as it is conducive for understanding possibilities for relational leadership because there is no formal hierarchy. By applying three aspects of a relational leadership perspective (mutual influence process [1], momentary [2] and socially co-constructed [3]) to a thematic analysis of interview data, understanding is developed about the potential dynamics of influence and leadership in non-hierarchical organising. Two contributions to relational leadership theory are offered. Firstly, the paper shows a need for greater critical attention to appreciate the potential subtleties and tensions involved in influencing dynamics in non-hierarchical organising; and, secondly, assumptions about the continuous potential for fluidity of influencing are challenged

Glyphosate efficacy, absorption and translocation for Eragrostis plana control.

Abstract: Background: Glyphosate is the most effective herbicide to control the invasive and perennial Eragrostis plana in Southern Brazil. However, one application has not been sufficient to prevent the regrowth of plants. Objective: The aim of this research was to evaluate the efficacy of glyphosate sprayed alone or mixed with fluazifop-p-butyl or flumioxazin on E. plana control and to investigate 14C-glyphosate absorption and translocation. Methods: Plants with 2-3 tillers were treated with glyphosate (700 g a.e. ha- 1), fluazifop-p-butyl (47 g a.i. ha-1), flumioxazin (100 g a.i. ha-1), glyphosate + fluazifop-p-butyl (700 g a.e. ha-1 + 47g a.i. ha-1), glyphosate + flumioxazin (700 g a.e. ha-1 +100 g a.i. ha-1). Weed control was evaluated visually for 28 d after treatment (DAT) when plants were harvested for shoot dry biomass determination. 14C-glyphosate absorption and translocation were measured at 24 and 72 h after treatment. Results: Glyphosate at 700 g a.e. ha-1 controlled E. plana plants at 2-3 tillers. The mixture with fluazifop-p-butyl or flumizin did not significantly increase the level of control (87 and 86% at 7 DAT, respectively) but increased 14C-glyphosate translocation to the roots. Conclusions: Glyphosate is effective on E. plana. However, applied with fluazifop-p-butyl could improve the control of this weed, especially when perennial plants of E. plana dominate the field, preventing their fast regrowth. Keywords: 14C-glyphosate; fluazifop-p-butyl; forage grass; invasive plant; tough lovegras

Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η 6-bip)Os(4-CO 2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η 6-p-cym)RuCl(dap)] + (p-cym = p-cymene) (5), and [(η 6-p-cym)RuCl(imidazole-CO 2H)(PPh 3)] + (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC 50 = 63 ± 2 μ in MCF-7 cells and IC 50 = 26 ± 3 μ in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 ± 2.6 μ in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society

Work-Unit Absenteeism: Effects of Satisfaction, Commitment, Labor Market Conditions, and Time

Prior research is limited in explaining absenteeism at the unit level and over time. We developed and tested a model of unit-level absenteeism using five waves of data collected over six years from 115 work units in a large state agency. Unit-level job satisfaction, organizational commitment, and local unemployment were modeled as time-varying predictors of absenteeism. Shared satisfaction and commitment interacted in predicting absenteeism but were not related to the rate of change in absenteeism over time. Unit-level satisfaction and commitment were more strongly related to absenteeism when units were located in areas with plentiful job alternatives

"I have got something positive out of this situation": psychological benefits of caregiving in relatives of young people with muscular dystrophy.

This paper focuses on the psychological benefits of caregiving in key relatives of patients with muscular dystrophies (MD), a group of rare diseases characterized by progressive weakness and restriction of the patient's functional abilities. We describe whether relatives perceived caregiving to be a positive experience and test whether relatives' perceptions vary in relation to their view of the patient as a valued person, the degree of involvement in care, and the level of support provided by social network and professionals. The study sample included 502 key relatives of patients aged 4-25 years, suffering from Duchenne, Becker, or limb-girdle MD, in treatment for at least 6 months to one of the eight participating centers, living with at least one relative aged 18-80 years. Of key relatives, 88 % stated that they had gotten something positive out of the situation, 96 % considered their patients to be sensitive, and 94 % viewed their patients as talented. Positive aspects of caregiving were more recognized by key relatives who were more convinced that the patient was sensitive and who perceived that they received higher level of professional help and psychological social support. These results suggest that most key relatives consider that their caregiving experience has had a positive impact on their lives, despite the practical difficulties of caring for patients with MD. Professionals should help relatives to identify the benefits of caregiving without denying its difficulties. Clinicians themselves should develop positive attitudes towards family involvement in the care of patients with long-term diseases

Farmer attitudes and livestock disease: exploring citizenship behaviour and peer monitoring across two BVD control schemes in the UK

The eradication of BVD in the UK is technically possible but appears to be socially untenable. The following study explored farmer attitudes to BVD control schemes in relation to advice networks and information sharing, shared aims and goals, motivation and benefits of membership, notions of BVD as a priority disease and attitudes toward regulation. Two concepts from the organisational management literature framed the study: citizenship behaviour where actions of individuals support the collective good (but are not explicitly recognised as such) and peer to peer monitoring (where individuals evaluate other’s behaviour). Farmers from two BVD control schemes in the UK participated in the study: Orkney Livestock Association BVD Eradication Scheme and Norfolk and Suffolk Cattle Breeders Association BVD Eradication Scheme. In total 162 farmers participated in the research (109 in-scheme and 53 out of scheme). The findings revealed that group helping and information sharing among scheme members was low with a positive BVD status subject to social censure. Peer monitoring in the form of gossip with regard to the animal health status of other farms was high. Interestingly, farmers across both schemes supported greater regulation with regard to animal health, largely due to the mistrust of fellow farmers following voluntary disease control measures. While group cohesiveness varied across the two schemes, without continued financial inducements, longer-term sustainability is questionabl

Inter-team Coordination in Large-Scale Agile Development: A Case Study of Three Enabling Mechanisms

Agile methods are increasingly used in large development projects, with multiple development teams. A central question is then what is needed to coordinate feature teams efficiently. This study exam- ines three mechanisms for coordination: Shared mental models, commu- nication and trust in a large-scale development project with 12 feature teams running over a four-year period. We analyse the findings in rela- tion to suggested frameworks for large-scale agile development and a theory on coordination, and provide new recommendations for practice and theory.Inter-team Coordination in Large-Scale Agile Development: A Case Study of Three Enabling MechanismspublishedVersio