Protective effects of intermedin/adrenomedullin-2 in a cellular model of human pulmonary arterial hypertension.

Proliferation of pulmonary fibroblasts (PF) and distal migration of smooth muscle cells (PSM) are hallmarks of pulmonary arterial hypertension (PAH). Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the Calcitonin Gene-Related Peptide (CGRP)/Adrenomedullin (AM) superfamily. These peptides act via Calcitonin-Like Receptors (CLR) combined with one of three Receptor activity-modifying proteins (RAMPs). IMD/AM2 is a potent pulmonary vasodilator in animal studies. The aim was to describe expression of IMD/AM2, AM and receptor components in human pulmonary vascular cells and to elucidate effects of IMD/AM2 on human PSM migration and PF proliferation. Gene expression was detected by immunofluorescence, immunoblotting and qRT-PCR. Normotension and hypertension were simulated by applying pulsatile mechanical stretch (Flexcell® apparatus). Viable cell numbers were determined by dye exclusion. PSM chemotaxis was measured via Dunn chamber. IMD/AM2 protein was co-expressed with AM and their receptor components in pulmonary artery and microvascular endothelial (PAEC, PMVEC) and non-endothelial cells (PF, PSM), and localised to vesicles. IMD/AM2 was secreted under basal conditions, most abundantly from PF and PMVEC. Secretion from PF and PSM was enhanced by stretch. IMD/AM2 mRNA expression increased in response to hypertensive stretch of PSM. IMD/AM2 inhibited PDGF (10-7 M)-mediated PSM migration maximally at 3 × 10-10 M and PF proliferation maximally at 3 × 10-9 M. Angiotensin II (5 × 10-8 M), normotensive and hypertensive stretch augmented PF proliferation. IMD/AM2 (10-9 M) abolished the proliferative effects of Angiotensin II and normotensive stretch and attenuated the proliferative effect of hypertensive stretch alone and combined with angiotensin II. These findings indicate an important counter-regulatory role for IMD/AM2 in PAH.

Reduction of catheter-related colonisation by the use of a silver zeolite-impregnated central vascular catheter in adult critical care.

Central vascular catheters (CVC) are used extensively in critical care for monitoring and therapy. They can become colonised with viable micro-organisms within 24 h of insertion, which can rapidly form biofilm. This colonisation is a precursor of catheter-related bloodstream infections (CR-BSI), which are associated with substantial morbidity, mortality, prolonged hospital stay and increased cost. Antimicrobials have been incorporated into the bulk material of CVC or applied to their surfaces as a coating in an attempt to reduce the incidence of CVC colonisation and infection. This study examines the effect of a silver zeolite-impregnated catheter on catheter-related colonisation and infection in adult critical care patients. The study was conducted in adult Intensive Care Units (ICU) at three acute hospitals over 14 months and involved 246 CVC insertions (122 silver-impregnated and 124 non-impregnated). CVC tip colonisation was detected by the Maki Roll culture and CR-BSI by differential time-to-positivity of blood cultures. Overall colonisation rate was significantly lower in the silver zeolite-impregnated CVC tips (58%) as compared with the control CVC tips (73%) (p<0.025). In addition, there was a lower rate (34%) of tip colonisation by coagulase negative staphylococci in the silver zeolite-impregnated CVC tips as compared with the control CVC tips (47%) (p<0.05). Four episodes of CR-BSI were detected in each arm by differential time-to-positivity in a subset of patients. This study indicates that the silver zeolite-impregnated catheter is superior to non-impregnated catheter in reducing the rate of CVC colonisation but it showed no difference in the rates of CR-BSI in the two arms. Larger prospective randomised control studies are required to evaluate its role in the prevention of CR-BSI.

Aging is associated with increased matrix metalloproteinase-2 activity in the human aorta.

BACKGROUND: Aging is a major risk factor for the development of arterial stiffness and vascular disease, and it is related to the upregulation of matrix metalloproteinase-2 (MMP-2) in the aorta of rats and nonhuman primates. This study aimed to determine whether MMP activity in the human vasculature changes with aging. We also assessed regional differences in MMP activity at two locations in the arterial tree, the aorta and the internal mammary artery (IMA). METHODS: Both MMP-2 and MMP-9 activity in the human aorta and IMA were determined by gelatin zymography and were localized within the tissue using in situ zymography. Tissue inhibitor of metalloproteinase-2 (TIMP-2) levels was determined by Western blot. RESULTS: Active MMP-2 (but not pro-MMP-2, pro-MMP-9, or active MMP-9) was positively correlated with age in the human aorta (r = 0.65; P < .001) but not in the IMA. Active MMP-2 and TIMP-2 (but not pro-MMP-2 or pro- or active MMP-9) levels are higher in the aorta than in the IMA (P < .001; P < .05). In the aorta, MMP activity is highest in the intima and is also detectable in the media and adventitia. To a lesser extent, MMP activity is present in all layers of the IMA. CONCLUSIONS: This study demonstrates that age-related MMP-2 upregulation occurs in the human aorta but not in the IMA.

Evaluation of level 1 care facilities for vascular patients.

BACKGROUND: A surgical acute care unit (SACU) was established within our hospital to specifically provide level 1 care to surgical patients. We assess the impact that this has had on outcome in vascular patients. METHODS: All patients undergoing carotid endarterectomy (CEA) and elective abdominal aortic aneurysm repair (AAA) during the first year of SACU were included in the present study. A control group was compiled from patients undergoing the same two procedures in the year preceding the opening of the SACU. Data were collected on admission time, time spent in critical care, outcome and operative cancellations. RESULTS: During the first year of the SACU there were 28 CEA and 42 AAA repairs performed. In the control group there were 18 CEA and 34 AAA repairs performed. There were no significant differences in death rate or length of hospital stay between the two groups for either AAA repair or CEA. CEA patients in the study group had a significantly reduced level 2 stay (P < 0.001 Mann-Whitney U-test), with 71% of patients being admitted directly to the level 1 facility from theatre. There were less CEA cancelled because of critical care bed shortages among the cases (n = 0) compared to the control group (n = 2), although this did not reach statistical significance (P = 0.15 Fisher's exact test). CONCLUSIONS: Designated level 1 care has reduced the need for the postoperative admission of CEA patients to level 2 care facilities. It has had no discernible impact on admission time or mortality, but might reduce the number of cancelled operations caused by a lack of level 2 beds.

Aspartame: review of safety.

Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.