Objective. The cannabinoid receptor CB2 is predominantly expressed in non-neuronal tissue and exerts potent immunomodulatory effects. This study was undertaken to evaluate the role of CB2 in the pathogenesis of dermal fibrosis.Methods. Mice deficient in CB2 (CB2 ؊/؊ mice) and their wild-type littermates (CB2 ؉/؉ mice) were injected with bleomycin to induce experimental fibrosis. Mice were treated with selective agonists and antagonists of CB2. Lesional skin was evaluated for dermal thickness and numbers of infiltrating leukocytes. Bone marrow transplantation experiments were performed.Results. CB2 ؊/؊ mice were more sensitive to bleomycin-induced dermal fibrosis than were CB2 ؉/؉ mice, and showed increased dermal thickness. Leukocyte counts were significantly higher in the lesional skin of CB2 ؉/؉ mice. Increased dermal fibrosis was also observed upon treatment with the CB2 antagonist AM-630. In contrast, the selective CB2 agonist JWH-133 reduced leukocyte infiltration and dermal thickening. The phenotype of CB2 ؊/؊ mice was mimicked by transplantation of CB2
SummaryFour different mechanisms for translation initiation are known, i.e. one prokaryotic mechanism involving a Shine-Dalgarno sequence, two eukaryotic mechanisms relying on ribosomal scanning or internal ribosomal entry sites, and one mechanism acting on leaderless transcripts. Recently it was reported that the majority of haloarchaeal transcripts is leaderless and that most leadered transcripts are devoid of a Shine-Dalgarno sequence, excluding the operation of a 'bacterial-like' initiation mechanism. Therefore, the current study concentrated on elucidating whether a 'eukaryotic-like' scanning mechanism might operate instead. GUG and UUG were efficiently used as start codons on leadered transcripts in vivo, in contrast to initiation on leaderless transcripts (and leadered eukaryotic transcripts). Deleted versions of the 5Ј-UTR initiated translation very inefficiently. Introduction of additional upstream AUGs did not influence the initiation efficiency at internal start codons. An additional in-frame AUG at the 5Ј-end led to the simultaneous usage of two start sites on the same message. A stable stem-loop structure at the 5Ј-end inhibited only initiation at the first AUG, but did not influence usage of the internal AUG. Taken together, operation of a scanning mechanism was excluded and the results indicate that a novel mechanism for translation initiation operates at least in haloarchaea.
Abstract. Plasma protein binding of antimicrobial agents is considered to be a key characteristic of antibiotics as it affects both their pharmacokinetics and pharmacodynamics. However, up to the present, no standard methods for measuring protein binding or for quantification of the influence of protein binding on antimicrobial activity exist. This short-coming has previously led to conflicting results on antibacterial activity of highly protein-bound antibiotics. The present review, therefore, set out to summarize (1) methods for quantification of protein binding, (2) microbiological growth media used for determination of the impact of protein binding on antimicrobial activity of antibiotics, and (3) different pharmacodynamic in vitro studies that are used in this context. The advantages and disadvantages of a wide range of different approaches are discussed and compared. The urgent call for international standardization by microbiological societies and laboratories may be considered as a logical consequence of the presented data.
Objectives:The aim of this study was to calculate the horizontal growth rate of melanoma in vivo and to correlate it with morphologic findings. Patients and Methods: We searched our database for melanomas for which sequential dermatoscopic images and histopathologic slides were available. The final sample consisted of 50 melanomas of 48 patients (mean age: 50 ± 15 years, 62% females). We calculated the horizontal growth rate in mm 2 per year by morphometric analysis of digital dermatoscopic images. Dermatoscopic and dermatopathologic findings were assessed according to predefined criteria and correlated with the horizontal growth rate. Results: The median time interval between baseline and follow-up image was 12 months (range: 2-100 months). The majority of melanomas were in situ (n=28, 56%). The mean horizontal growth rate of all melanomas was 5.
Objective. Systemic sclerosis (SSc) is a connective tissue disease that is characterized by microvascular disease and tissue fibrosis. Progressive loss and irregular architecture of the small blood vessels are well characterized, but the potential involvement of the lymphatic vessel system has not been analyzed directly in SSc. This study was undertaken to assess whether the lymphatic vascular system is affected in SSc, and whether changes to the lymphatic vessels are associated with dystrophic changes and tissue damage in patients with SSc.Methods. Lymphatic endothelial cells in skin biopsy samples from patients with SSc and age-and sex-matched healthy volunteers were identified by staining for podoplanin and prox-1, both of which are specifically expressed in lymphatic endothelial cells but not in blood vascular endothelial cells. CD31 was used as a pan-endothelial cell marker. Statistical analyses were performed using Kruskal-Wallis, Mann-Whitney U, and Spearman's rank correlation tests.Results. The numbers of podoplanin-and prox-1-positive lymphatic vessels were significantly reduced in patients with SSc as compared with healthy individuals. The number of podoplanin-positive lymphatic precollector vessels was significantly lower in SSc patients with fingertip ulcers than in SSc patients without ulcers. Moreover, the number of lymphatic vessels correlated inversely with the number of fingertip ulcers at the time of biopsy and with the number of fingertip ulcers per year. The inverse correlation between lymphatic precollector vessel counts and fingertip ulcers remained significant after statistical adjustment for the blood vessel count, age, and modified Rodnan skin thickness score.Conclusion. These results demonstrate a severe reduction in the number of lymphatic capillaries and lymphatic precollector vessels in patients with SSc.
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