Disease Mechanisms in psoriasis and psoriatic arthritis

Any hypothesis that tries to explain disease mechanisms in psoriasis and psoriatic arthritis (PsA) must take into account the containment of the inflammatory process to three specific sites: the skin, synovium, and enthesis. This article reviews the recent literature that advances our understanding of disease mechanisms at these specific sites. Additional progress will be achieved by research that focuses on common pathogenic pathways at these sites, in particular when searching for foreign candidates or autoantigens triggering the T-cell-mediated immune response.     

Vectorization of morpholino oligomers by the (R-Ahx-R)4 peptide allows efficient splicing correction in the absence of endosomolytic agents.

The efficient and non-toxic nuclear delivery of steric-block oligonucleotides (ON) is a prerequisite for therapeutic strategies involving splice correction or exon skipping. Cationic cell penetrating peptides (CPPs) have given rise to much interest for the intracellular delivery of biomolecules, but their efficiency in promoting cytoplasmic or nuclear delivery of oligonucleotides has been hampered by endocytic sequestration and subsequent degradation of most internalized material in endocytic compartments. In the present study, we compared the splice correction activity of three different CPPs conjugated to PMO(705), a steric-block ON targeted against the mutated splicing site of human beta-globin pre-mRNA in the HeLa pLuc705 splice correction model. In contrast to Tat48-60 (Tat) and oligoarginine (R(9)F(2)) PMO(705) conjugates, the 6-aminohexanoic-spaced oligoarginine (R-Ahx-R)(4)-PMO(705) conjugate was able to promote an efficient splice correction in the absence of endosomolytic agents. Our mechanistic investigations about its uptake mechanisms lead to the conclusion that these three vectors are internalized using the same endocytic route involving proteoglycans, but that the (R-Ahx-R)(4)-PMO(705) conjugate has the unique ability to escape from lysosomial fate and to access to the nuclear compartment. This vector, which has displays an extremely low cytotoxicity, the ability to function without chloroquine adjunction and in the presence of serum proteins. It thus offers a promising lead for the development of vectors able to enhance the delivery of therapeutic steric-block ON in clinically relevant models.     

Effects of mycophenolic acid on IL-6 expression of human renal proximal and distal tubular cells in vitro.

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine which regulates immune responses and host defence mechanisms. IL-6 has been found to be increased in certain inflammatory conditions of the kidney, in which tubular epithelial cells play a pivotal role. Human renal tubular cells express IL-6. Until now no data about the effect of the immunosuppressant drug mycophenolic acid (MPA) on IL-6 expression were available. METHODS: Proximal and distal tubular epithelial cells (PTC/DTC) have been isolated immunomagnetically. Confluent monolayers were stimulated with interleukin-1beta (IL-1beta; 25 U/ml), IL-1beta+ MPA (0.25-50 micro M) or MPA alone for 48 h. Release of IL-6 protein into the supernatant was evaluated with an enzyme immunoassay, IL-6 mRNA expression was evaluated using the Quantikine mRNA kit. RESULTS: After IL-1beta stimulation, a highly significant 2.6- (PTC) and 3.8-fold (DTC) upregulation of IL-6 expression was detectable. IL-6 mRNA was upregulated by IL-1beta [1.57- (PTC) and 2.03-fold (DTC)]. MPA inhibited this cytokine-induced IL-6 expression in a dose-dependent manner. Incubation with the lowest MPA concentration had no effect on the stimulated upregulation, whereas all higher doses significantly decreased IL-6 expression. Dexamethasone significantly inhibited the cytokine-induced IL-6 protein release in PTC, but not in DTC. CONCLUSIONS: In this study we demonstrated for the first time an inhibitory effect of MPA on the stimulated IL-6 expression of renal tubular epithelial cells. In contrast to older data, which showed a synergistic upregulation of the expression of a CC-chemokine by a combination of cytokines and MPA, in the present study we could demonstrate an immunosuppressive effect of MPA on the expression of an important cytokine.     

The Effects of Depressed Affect on Functional Disability Among Rural Older Adults

This study investigates functional disability among some of the nation's most vulnerable older adults: rural Medicaid recipients. Data were provided by 221 older adults (mean age = 75.9 years; 82% women) who were receiving community-based long-term care services through Medicaid. Participants self-reported functional ability involving the completion of six basic activities of daily living (BADLs), three cognitive instrumental activities of daily living (IADLS), and four physical IADLs. Self-reports of depressed affect and the number of physical health conditions were also obtained. Path analysis was used to examine all of the associations among age, gender, number of chronic health conditions, depressed affect and functional disability. The tested model was significant [chi2 (DF = 3, n = 221) = 5.052, p = 0.168; TLI = 0.945; CFI = 0.992; RMSEA = 0.056] and explained 45.1% of the variance in BADL disability. Depressed affect significantly predicted disability in cognitive IADLs and physical IADLs, which predicted disability in BADLs. Age and gender had indirect effects on BADL, through their association with cognitive IADLs and physical IADLs. The number of chronic health conditions exerted both indirect and direct effects on BADL disability. Results are discussed within the context of the growing literature that suggests the importance of psychological variables as predictors of functional disability. Moreover, we discuss whether community-based long-term care is appropriate for older adults with high levels of functional disability.     

High-resolution myocardial perfusion mapping in small animals in vivo by spin-labeling gradient-echo imaging.

An ECG and respiration-gated spin-labeling gradient-echo imaging technique is proposed for the quantitative and completely noninvasive measurement and mapping of myocardial perfusion in small animals in vivo. In contrast to snapshot FLASH imaging, the spatial resolution of the perfusion maps is not limited by the heart rate. A significant improvement in image quality is achieved by synchronizing the inversion pulse to the respiration movements of the animals, thereby allowing for spontaneous respiration. High-resolution myocardial perfusion maps (in-plane resolution=234 x 468 microm2) demonstrating the quality of the perfusion measurement were obtained at 4.7 T in a group of seven freely breathing Wistar-Kyoto rats under isoflurane anesthesia. The mean perfusion value (group average +/- SD) was 5.5 +/- 0.7 ml g(-1)min(-1). In four animals, myocardial perfusion was mapped and measured under cardiac dobutamine stress. Perfusion increased to 11.1 +/- 1.9 ml g(-1)min(-1). The proposed method is particularly useful for the study of small rodents at high fields.     

Burnout in nursing.

OBJECTIVE: Previous research has suggested that organisational change can contribute to stress-related outcomes for workers. Burnout, one such stress-related outcome, has been conceptualised as a multidimensional construct consisting of emotional exhaustion, depersonalisation and reduced personal accomplishment. Many health care organisations have undergone substantial organisational change over the last decade. The purpose of this study was to assess levels of burnout in nurses and to ascertain if there were individual or work characteristics that were associated with this syndrome. DESIGN: Randomised survey methodology. SETTING: Registered nurses (Division 1) in Victoria who were ANF members. SUBJECTS: A random sample of 574 Victorian ANF nurse members. MAIN OUTCOME MEASURES: The assessment of levels of burnout in Victorian ANF nurse members and the identification of individual or work characteristics that may be associated with it. RESULTS: Victorian ANF nurse members exhibited lower depersonalisation and higher personal accomplishment compared to medical and overall normative data. Increasing age and fewer working hours were associated with lower levels of emotional exhaustion and depersonalisation. Working overtime was positively associated with emotional exhaustion however further analyses demonstrated that those who worked overtime voluntarily did not differ from workers not working overtime. However feeling pressured/expected to work overtime was positively associated with emotional exhaustion and depersonalisation. CONCLUSION: Victorian ANF nurse members were not experiencing high levels of burnout. However the study highlighted the need for health care management to recognise the importance of working reasonable hours and in particular, to understand the potential detrimental effect that having to work pressured or unexpected overtime has on staff.