Development of Feline Immunodeficiency Virus ORF-A (tat) Mutants: In Vitro and in Vivo Characterization

AbstractA functional ORF-A is essential for efficient feline immunodeficiency virus replication in lymphocytes. We have characterized a series of mutants of the Petaluma strain, derived from p34TF10 and having different combinations of stop codons and increasingly long deletions in ORF-A. Six clones proved fully replicative in fibroblastoid Crandell feline kidney cells and monocyte-derived macrophage cultures but failed to replicate in T cell lines and primary lymphoblasts. Cats inoculated with three selected mutants had considerably milder infections than controls given intact ORF-A virus. In vivo, the mutants maintained growth properties similar to those in vitro for at least 7 months, except that replication in lymphoid cells was strongly reduced but not ablated. One mutant underwent extensive ORF-A changes without, however, reverting to wild-type. Antiviral immune responses were feeble in all cats, suggesting that viral loads were too low to represent a sufficiently powerful antigenic stimulus

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

Comparison of primary human gingival fibroblasts from an older and a young donor on the evaluation of cytotoxicity of denture adhesives

Denture adhesives (DA) improve the retention and stability of ill-fitting dentures, especially for older adults. These materials should be biocompatible, i.e., they cannot cause undesired biological responses and be non-cytotoxic to oral tissues. However, in vitro testing of DA biocompatibility employing primary cell culture may possibly be affected by other factors, such as the donor age. Objective To compare the cytotoxicity of three different denture adhesives when assessed in primary gingival fibroblasts from a young donor or from an older donor, as well as the release of the basic fibroblast growth factor (bFGF), and the inflammatory response marker interleukin-6 (IL-6). Material and Methods Gingival fibroblasts isolated from a 30- and a 62-year-old donor were assayed for proliferation (1-7 days) and sensitivity to latex (positive control). Fibroblasts were indirectly exposed to Corega Ultra (cream), Corega powder and Fixodent Original for a 24 h period and assayed by XTT and Crystal Violet tests. The release of IL-6 and bFGF by exposed cells was determined by ELISA. Results While cells from the young donor presented higher cell growth after 7 days, the sensitivity to increasing concentrations of latex extracts was very similar between young and older cells. Both XTT and CVDE detected no difference between the DA and the control group. All materials induced higher levels of IL-6 and bFGF compared to control. Cells from the older donor exposed to Corega Ultra released lower levels of cytokine and growth factor. Conclusions All materials were considered non-cytotoxic, but affected cytokine and growth factor release. The biological differences found between fibroblasts from both donors could be due to individual or age-related factors. The authors suggest the use of cells from older donors on studies of dental products aimed at older patients, to better simulate their physiological response

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

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

Intergroup conflict management strategies from a nobel peace laureate: The case of Jose Ramos-Horta

We report on the case of Dr. José Ramos-Horta (JRH), a 1996 Nobel Peace Laureate, former President of East Timor, and current envoy of the United Nations to Guinea-Bissau. JRH agreed to an interview detailing the peace building strategies he has used to manage conflicts. The transcript of his Nobel Laureate acceptance speech was also analysed to strengthen the overall narrative. Our findings suggest two higher-order themes: (1) psycho-social skills, and (2) social networking. Specifically, JRH uses active listening, mindful breaks, and awareness of media trends to create personal and strategic networking contacts, which are critical elements in managing conflict

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

A koherencia mint a lelki és testi egészség alapvető meghatározója a mai magyar társadalomban = Sense of coherence as an important determinant of mental and physical health

Az ún. salutogenezis modell olyan keretet kínál, amelyben a koherencia élmény bevezetésével lehetőség nyílik az „egész”-ség dinamikus értelmezésére. Vizsgálatunkban a Richard Rahe-féle, az „élet értelme” koherencia kérdőív összefüggéseit vizsgáltuk az egészségi állapottal. A Hungarostudy 2002 felmérés a 18 évesnél idősebb magyar népességet életkor, nem és terület szerint képviseli. 12 640 személlyel vettünk fel otthoni interjút. Az így vizsgált koherencia mutatót az egészségi állapot igen fontos előrejelzőjének találtuk. Ha az adatokat életkor, nem és iskolázottság szerint korrigáltuk, az egészségi állapot önbecslése mintegy 10-szer, a munkaképesség 8-szor jobb, a depresszió valószínűsége 7-szer alacsonyabb volt. Az „élet értelme” mutató igen szoros kapcsolatban áll az önhatékonysággal, a problémaorientált megbirkózással, a társas támogatással, ezzel szemben kevésbé függ az iskolázottságtól, az életkortól és a nemtől