Differential effects of olmesartan and ramipril on inflammatory response after myocardial infarction in rats

This study compares the effect of two different strategies to inhibit the renin-angiotensin system in the setting of acute myocardial infarction (MI). Male Wistar rats were treated with placebo, the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg/day), or the AT1 receptor antagonist, olmesartan (1 mg/kg/day), both initiated 1 week before induction of MI and continued for 6 weeks after MI. The inflammatory reaction in the heart was investigated 7 days post-MI by determination of macrophage infiltration and the expression of tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta and IL-6 at mRNA and protein levels. Six weeks post-MI, cardiac function was measured following chronic implantation of catheters in the LV and femoral artery, and cardiac morphology and coronary structure were investigated in picrosirius-red stained hearts. In placebo-treated rats, macrophage infiltration was accompanied by upregulation of IL-1beta and IL-6 mRNA in the peri-infarct zone. TNF-alpha and IL-1beta mRNA and protein were also upregulated in the non-infarcted myocardium. Whereas both treatment regimes significantly reduced IL-6 upregulation, olmesartan additionally reduced macrophage infiltration and IL-1beta expression. Six weeks post-MI, placebo-treated MI animals developed an impaired cardiac function with structural remodeling of the myocardium and coronaries. While olmesartan and ramipril both improved cardiac function and reduced infarct size and myocardial/coronary remodeling, olmesartan was more effective not only in increasing vascular perimeter, inner vascular diameter and septal thickness but also in lowering media thickness of coronary arteries, inner left ventricular diameter, left ventricular circumference and left ventricular end-diastolic pressure than ramipril. Thus, following MI the AT1 receptor blocker, olmesartan, attenuated cardiac inflammatory reactions and protected myocardial/coronary structure and function of the failing heart proving to be of similar, in some cases superior effectiveness in this respect than the ACE inhibitor, ramipril.     

Adventitial VEGF165 gene transfer prevents lumen loss through induction of positive arterial remodeling after PTCA in porcine coronary arteries

Negative arterial remodeling still plays an important role in the pathogenesis of coronary restenosis even in the era of interventional stenting (e.g. arterial narrowing occurs proximal and distal of a stented segment). Previous studies suggest that increased angiogenesis and inhibited regression of injury-induced adventitial microvessels prevents negative remodeling. We have examined the effect of local vascular endothelial growth factor (VEGF(165)) gene transfer on adventitial microvessel angiogenesis/regression and arterial remodeling after coronary angioplasty. Twenty pigs underwent angioplasty, each one in two major coronary arteries, followed by plasmid liposome gene transfer with either VEGF(165) or control gene LacZ (50 microg DNA with 50 microg of Lipofectine) into the (peri)adventitial space using a needle injection catheter. Arteries were examined at days 1, 7, 14, and 28. Local delivery of VEGF(165) gene into the outer compartments of balloon-injured porcine coronary arteries reduced lumen area loss due to distinct positive remodeling (arterial enlargement). Prevention of adventitial microvessel regression, enhanced adventitial elastin accumulation, reduced adventitial myofibroblast numbers, and a pronounced adventitial inflammatory response considered as a part of arterial healing seem to be the main VEGF-mediated mechanisms indicating the therapeutic potential of VEGF for restenosis prevention.     

Evaluation of a computed-tomography-based assessment scheme in treatment decision-making for isolated orbital floor fractures

Introduction

Treatment decisions for fractures of the orbital floor are based on clinical appearance, ophthalmological examination, and computed tomography (CT) scans. In extensive fractures, decisions are easily made between conservative and surgical treatment. However, objective parameters are rare in inconclusive cases.

Cost analyses of community-acquired pneumonia from the hospital perspective

STUDY OBJECTIVES: Community-acquired pneumonia (CAP) is a widespread disease with important implications for health-care systems worldwide. This study investigated direct costs, treatment patterns, and outcomes associated with two patient cohorts hospitalized with CAP. DESIGN: The study design was naturalistic, prospective, and open. PATIENTS: The study enrolled 580 patients. Two hundred sixty-one patients were treated initially with IV moxifloxacin (45%, cohort M); the remaining 319 patients received nonstandardized treatment (cohort S). SETTING: Twenty-two hospitals in Germany. RESULTS: Clinical success rates were similar between treatment groups (cohort M, 242 of 256 patients, 95%; cohort S, 286 of 312 patients, 92%; p = 0.208). Mean +/- SD length of hospital stay was 10.8 +/- 5.2 days, with cohort M having a significantly shorter hospital stay (10.0 +/- 4 days) compared to cohort S (11.5 +/- 6 days; p < 0.001). Median of all direct costs was dollar 1,333 (minimum, dollar 127; maximum, dollar 9,488), with direct costs of dollar 1,250 in cohort M (minimum, dollar 372; maximum, dollar 9,488) and dollar 1,409 in cohort S (minimum, dollar 127; maximum, dollar 9,366) per treated episode of CAP (p = 0.066). CONCLUSIONS: Major determinants of costs were length of hospital stay and ICU admission, whereas costs for staff and hotel were major contributors to direct costs. Initial antibiotic therapy with moxifloxacin resulted in similar clinical efficacy and direct costs compared to nonstandardized therapy; however, patients treated with moxifloxacin benefited with an earlier hospital discharge.     

Risk in elderly patients after stentless versus stented aortic valve surgery

Recent studies suggest that the hemodynamic advantage of stentless bioprostheses over the stented type improves long-term survival after aortic valve replacement, but the more complex and time-consuming implantation technique may increase the risks of operative death and postoperative complications. Between April 1996 and June 2001, 519 patients with a mean age of 76 +/- 5 years underwent aortic valve replacement using a stentless (Medtronic Freestyle, n = 277) or stented bioprosthesis (Medtronic Mosaic, n = 242). Multiple logistic regression analysis considering different patient populations revealed no increased risk of operative death, postoperative complications, or neurological impairment after implantation of a stentless bioprosthesis. Survival curves in respect of 367 patients who underwent aortic valve replacement up to September 2000 and were followed up for 3 years were not different (p = 0.98). As the patients were elderly, improved survival due to implantation of a stentless valve could not be demonstrated within this time span.     

S100A1 in cardiovascular health and disease: Closing the gap between basic science and clinical therapy

Calcium (Ca²⁺) signaling plays a major role in a wide range of physiological functions including control and regulation of cardiac and skeletal muscle performance and vascular tone [1] and [2]. As all Ca²⁺ signals require proteins to relay intracellular Ca²⁺ oscillations downstream to different signaling networks, a specific toolkit of Ca²⁺-sensor proteins involving members of the EF-hand S100 Ca²⁺ binding protein superfamily maintains the integrity of the Ca²⁺ signaling in a variety of cardiac and vascular cells, transmitting the message with great precision and in a temporally and spatially coordinated manner [3], [4], [5] and [6]. Indeed, the possibility that S100 proteins might contribute to heart and vascular diseases was first suggested by the discovery of distinctive patterns of S100 expression in healthy and diseased hearts and vasculature from humans and animal heart failure (HF) models [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17] and [18]. Based on more elaborate genetic studies in mice and strategies to manipulate S100 protein expression in human cardiac, skeletal muscle and vascular cells, it is now apparent that the integrity of distinct S100 protein isoforms in striated muscle and vascular cells such as S100A1, S100A4, S100A6, S100A8/A9 or S100B is a basic requirement for normal cardiovascular and muscular development and function; loss of integrity would naturally lead to profound deregulation of the implicated Ca²⁺ signaling systems with detrimental consequences to cardiac, skeletal muscle, and vascular function [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19] and [20]. The brief debate and discussion here are confined by design to the biological actions and pathophysiological relevance of the EF-hand Ca²⁺-sensor protein S100A1 in the heart, vasculature and skeletal muscle with a particular focus on current translational therapeutic strategies [4], [21] and [23]. By virtue of its ability to modulate the activity of numerous key effector proteins that are essentially involved in the control of Ca²⁺ and NO homeostasis in cardiac, skeletal muscle and vascular cells, S100A1 has been proven to play a critical role both in cardiac performance, blood pressure regulation and skeletal muscle function [4,21,23]. Given that deregulated S100A1 expression in cardiomyocytes and endothelial cells has recently been linked to heart failure and hypertension [4,21,23], it is arguably a molecular target of considerable clinical interest as S100A1 targeted therapies have already been successfully investigated in preclinical translational studies.     

The HIV 5′ Gag Region Displays a Specific Nucleotide Bias Regulating Viral Splicing and Infectivity

Alternative splicing and the expression of intron-containing mRNAs is one hallmark of HIV gene expression. To facilitate the otherwise hampered nuclear export of non-fully processed mRNAs, HIV encodes the Rev protein, which recognizes its intronic response element and fuels the HIV RNAs into the CRM-1-dependent nuclear protein export pathway. Both alternative splicing and Rev-dependency are regulated by the primary HIV RNA sequence. Here, we show that these processes are extremely sensitive to sequence alterations in the 5’coding region of the HIV genomic RNA. Increasing the GC content by insertion of either GFP or silent mutations activates a cryptic splice donor site in gag, entirely deregulates the viral splicing pattern, and lowers infectivity. Interestingly, an adaptation of the inserted GFP sequence toward an HIV-like nucleotide bias reversed these phenotypes completely. Of note, the adaptation yielded completely different primary sequences although encoding the same amino acids. Thus, the phenotypes solely depend on the nucleotide composition of the two GFP versions. This is a strong indication of an HIV-specific mRNP code in the 5′ gag region wherein the primary RNA sequence bias creates motifs for RNA-binding proteins and controls the fate of the HIV-RNA in terms of viral gene expression and infectivity.