Bioactive properties of iron-containing carbon monoxide-releasing molecules

Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls [tricarbonyldichloro ruthenium(II) dimer and tricarbonylchloro-(glycinato)ruthenium(II)] and boronacorbonates (sodium boranocarbonate) have been shown to promote vasodilatory, cardioprotective, and anti-inflammatory activities in a variety of experimental models. Here, we extend our previous studies by showing that η-4-(4-bromo-6-methyl-2-pyrone)tricarbonyl iron (0) (CORM-F3), an irontricarbonyl complex that contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (e.g., nitrite production) of RAW264.7 macrophages stimulated with endotoxin in a dose-dependent fashion. By

BIOACTIVE PROPERTIES OF IRON-CONTAINING CARBON

Carbon monoxide-releasing molecules (CO-RMs) are compounds capable of delivering controlled amounts of CO within a cellular environment. Ruthenium-based carbonyls (CORM-2 and CORM-3) and boronacorbonates (CORM-A1) have been shown to promote vasodilatory, cardioprotective and anti-inflammatory activities in a variety of experimental models. Here we extend our previous studies by showing that CORM-F3, an irontricarbonyl complex which contains a 2-pyrone motif, liberates CO in vitro and exerts pharmacological actions that are typical of CO gas. Specifically, CORM-F3 caused vasorelaxation in isolated aortic rings and inhibited the inflammatory response (eg nitrite production) of RAW264. 7 macrophages stimulated with endotoxin in a dose-dependent fashion. By analyzing the rate of CO release, we found that when the bromide at the 4-position of the 2-pyrone in CORM-F3 is substituted with a chloride group (CORM-F8), the rate of CO release is significantly decreased (4.5 fold) and a further decrease is observed when the 4-and 6-positions are substituted with a methyl group (CORM-F11) or a hydrogen (CORM-F7), respectively. Interestingly, the compounds containing halogens at the 4-position and the methyl at the 6-position of the 2-pyrone ring (CORM-F3 and CORM-F8) were found to be less cytotoxic compared to other CO-RMs when tested in RAW246. 7 macrophages. Thus, iron-based carbonyls mediate pharmacological responses that are achieved through liberation of CO and the nature of the substituents in the organic ligand have a profound effect on both the rate of CO release and cytotoxicity

Do quantitative and qualitative shear wave elastography have a role in evaluating musculoskeletal soft tissue masses?

Objectives: To determine if quantitative and qualitative shear wave elastography have roles in evaluating musculoskeletal masses. Methods: 105 consecutive patients, prospectively referred for biopsy within a specialist sarcoma centre, underwent B-mode, quantitative (m/s) and qualitative (colour map) shear wave elastography. Reference was histology from subsequent biopsy or excision where possible. Statistical modelling was performed to test elastography data and/or B-mode imaging in predicting malignancy. Results: Of 105 masses, 39 were malignant and 6 had no histology but benign characteristics at 12 months. Radiologist agreement for B-mode and elastography was moderate to excellent Kw 0.52-0.64; PABAKw 0.85-0.90). B-Mode imaging had 78.8% specificity, 76.9% sensitivity for malignancy. Quantitatively, adjusting for age, B-mode and lesion volume there was no statistically significant association between longitudinal velocity and malignancy (OR [95% CI] 0.40[0.10, 1.60], p=0.193), but some evidence that higher transverse velocity was associated with decreased odds of malignancy (0.28[0.06, 1.28], p=0.101). Qualitatively malignant masses tended to be towards the blue spectrum (lower velocities); 39.5% (17/43) of predominantly blue masses were malignant, compared to 14.3% (1/7) of red lesions. Conclusions: Quantitatively and qualitatively there is no statistically significant association between shear wave velocity and malignancy. There is no clear additional role to B-mode imaging currently. Key Points: • Correlation between shear wave velocity and soft tissue malignancy was statistically insignificant• B-mode ultrasound is 76.9 % sensitive and 78.8 % specific• Statistical models show elastography does not significantly add to lesion assessmen

Retention of basic laparoscopic skills after a structured training program

The purpose of this study was to test the retention of basic laparoscopic skills on a box trainer 1 year after a short training program. For a prior study, eight medical students without prior experience (novices) underwent baseline testing, followed by five weekly training sessions and a final test. During each of seven sessions, they performed five tasks on an inanimate box trainer. Scores were calculated by adding up the time to completion of the task with penalty points, consequently rewarding speed and precision. The sum score was the sum of the five scores. One year later, seven of them underwent retention testing for the current study. The final test results were compared with retention test results as a measure of durability of acquired skills. Novices’ scores did not worsen significantly for four out of five tasks (i.e., placing a pipe cleaner p = 0.46, placing beads p = 0.24, cutting a circle p = 0.31, and knot tying p = 0.13). However, deterioration was observed in the performance on stretching a rubber band (p < 0.05), as well as in the sum score (p < 0.05). Nevertheless, all retention scores remained better than the baseline results. In conclusion, basic laparoscopic skills acquired during a short training program merely sustain over time. However, ongoing practice is advisable, especially to preserve tissue-handling skills, since these may be the first to deteriorate

Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours

Wilms' tumour is one of the most common solid tumours of childhood. 11p13 (WT1 locus) and 11p15.5 (WT2 locus) are known to have genetic or epigenetic aberrations in these tumours. In Wilms' tumours, mutation of the Wilms tumour 1 (WT1) gene at the WT1 locus has been reported, and the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1, can undergo maternal deletion or alterations associated with imprinting. Although these alterations have been identified in many studies, it is still not clear how frequently combined genetic and epigenetic alterations of these loci are involved in Wilms' tumours or how these alterations occur. To answer both questions, we performed genetic and epigenetic analyses of these loci, together with an additional gene, CTNNB1, in 35 sporadic Wilms' tumours. Loss of heterozygosity of 11p15.5 and loss of imprinting of IGF2 were the most frequent genetic (29%) and epigenetic (40%) alterations in Wilms' tumours, respectively. In total, 83% of the tumours had at least one alteration at 11p15.5 and/or 11p13. One-third of the tumours had alterations at multiple loci. Our results suggest that chromosome 11p is not only genetically but also epigenetically critical for the majority of Wilms' tumours

Robust Reproducible Resting State Networks in the Awake Rodent Brain

Resting state networks (RSNs) have been studied extensively with functional MRI in humans in health and disease to reflect brain function in the un-stimulated state as well as reveal how the brain is altered with disease. Rodent models of disease have been used comprehensively to understand the biology of the disease as well as in the development of new therapies. RSN reported studies in rodents, however, are few, and most studies are performed with anesthetized rodents that might alter networks and differ from their non-anesthetized state. Acquiring RSN data in the awake rodent avoids the issues of anesthesia effects on brain function. Using high field fMRI we determined RSNs in awake rats using an independent component analysis (ICA) approach, however, ICA analysis can produce a large number of components, some with biological relevance (networks). We further have applied a novel method to determine networks that are robust and reproducible among all the components found with ICA. This analysis indicates that 7 networks are robust and reproducible in the rat and their putative role is discussed