The effect of bilateral internal thoracic artery harvesting on superficial and deep sternal infection: The role of skeletonization

Objective: To determine the relative risk of sternal dehiscence in patients undergoing bilateral internal thoracic artery harvesting and to assess whether and to what extent the technique of artery skeletonization might reduce this risk. Methods: Prospectively collected data on patients undergoing coronary artery bypass operations with at least a single internal thoracic artery were reviewed. The last 450 patients receiving bilateral internal thoracic artery grafts were compared with 450 patients who received a single internal thoracic artery during the same period. The left internal thoracic artery was always harvested in a pedicled fashion. Among patients receiving a bilateral internal thoracic artery, both arteries were harvested in a pedicled fashion in 300 cases, whereas both internal thoracic arteries were skeletonized in the remaining 150 cases. Results: Compared with a single internal thoracic artery, harvesting both internal thoracic arteries either in a skeletonized or in a pedicled fashion increased the chance of deep (1.1% vs 3.3% vs 4.7%; P =. 01) or superficial (4.8% vs 7.8% vs 12%; P =. 002) sternal infection. However, the technique of artery harvesting (odds ratio, 4.1; 95% confidence interval, 1.4-12.1); the presence of peripheral arteriopathy (odds ratio, 3.1; 95% confidence interval, 1.2-8.5), and resternotomy for bleeding (odds ratio, 8.2; 95% confidence interval, 2.0-33.6) were the only independent predictors for deep sternal infection, whereas the technique of artery harvesting (odds ratio, 3.0; 95% confidence interval, 1.6-5.4), female sex (odds ratio, 2.2; 95% confidence interval, 1.2-4.2), and diabetes (odds ratio, 1.7; 95% confidence interval, 1.0-2.9) were the only independent predictors of superficial sternal infection. In diabetic patients, there was no difference in the incidence of deep sternal infection among patients receiving a single internal thoracic artery or double skeletonized internal thoracic arteries (P =. 4). Conclusions: Bilateral internal thoracic artery harvesting carries a higher risk of sternal infection than harvesting a single internal thoracic artery. Skeletonization of both internal thoracic arteries significantly decreases this risk. A strategy of bilateral thoracic artery grafting can also be offered to patients at high risk for wound infection. Copyright © 2005 by The American Association for Thoracic Surgery

Inflammatory Cytokines Associated With Failure of Lower-Extremity Endovascular Revascularization (LER): A Prospective Study of a Population With Diabetes

OBJECTIVE Peripheral artery disease (PAD) is one of the most relevant complications of diabetes. Although several pharmacological and revascularization approaches are available for treating patients with diabetes and PAD, an endovascular approach is often associated with postprocedural complications that can increase the risk for acute limb ischemia or amputation. However, no definitive molecular associations have been described that could explain the difference in outcomes after endovascular treatment in patients with diabetes, PAD, and chronic limb-threatening ischemia (CLTI). RESEARCH DESIGN AND METHODS We evaluated the relationship between the levels of the main cytokines associated with diabetic atherosclerosis and the outcomes after endovascular procedures in patients with diabetes, PAD, and CLTI. RESULTS A total of 299 patients with below-the-knee occlusive disease who were undergoing an angioplasty procedure were enrolled. The levels of key cytokines—osteoprotegerin (OPG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP)—were measured, and major adverse limb events (MALE) and major adverse cardiovascular events (MACE) were assessed 1, 3, 6, and 12 months after the procedure. There was a linear trend from the lowest to the highest quartile for each cytokine at baseline and incident MALE. A linear association was also observed between increasing levels of each cytokine and incident MACE. Receiver operating characteristics models were constructed using clinical and laboratory risk factors, and the inclusion of cytokines significantly improved the prediction of incident events. CONCLUSIONS We demonstrated that elevated OPG, TNF-α, IL-6, and CRP levels at baseline correlate with worse vascular outcomes in patients with diabetes, PAD, and CLTI undergoing an endovascular procedure

Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer

The interaction between proteins is a fundamental event for cellular life that is generally mediated by specialized protein domains or modules. PDZ domains are the largest class of protein–protein interaction modules, involved in several cellular pathways such as signal transduction, cell–cell junctions, cell polarity and adhesion, and protein trafficking. Because of that, dysregulation of PDZ domain function often causes the onset of pathologies, thus making this family of domains an interesting pharmaceutical target. In this review article we provide an overview of the structural and functional features of PDZ domains and their involvement in the cellular and molecular pathways at the basis of different human pathologies. We also discuss some of the strategies that have been developed with the final goal to hijack or inhibit the interaction of PDZ domains with their ligands. Because of the generally low binding selectivity of PDZ domain and the scarce efficiency of small molecules in inhibiting PDZ binding, this task resulted particularly difficult to pursue and still demands increasing experimental efforts in order to become completely feasible and successful in vivo

Wee1 rather than plk1 is inhibited by AZD1775 at therapeutically relevant concentrations

Wee1 kinase is an inhibitor of cyclin-dependent kinase (cdk)s, crucial cell cycle progression drivers. By phosphorylating cdk1 at tyrosine 15, Wee1 inhibits activation of cyclin B-cdk1 (Cdk1), preventing cells from entering mitosis with incompletely replicated or damaged DNA. Thus, inhibiting Wee1, alone or in combination with DNA damaging agents, can kill cancer cells by mitotic catastrophe, a tumor suppressive response that follows mitosis onset in the presence of under-replicated or damaged DNA. AZD1775, an orally available Wee1 inhibitor, has entered clinical trials for cancer treatment following this strategy, with promising results. Recently, however, AZD1775 has been shown to inhibit also the polo-like kinase homolog Plk1 in vitro, casting doubts on its mechanism of action. Here we asked whether, in the clinically relevant concentration range, AZD1775 inhibited Wee1 or Plk1 in transformed and non-transformed human cells. We found that in the clinically relevant, nanomolar, concentration range AZD1775 inhibited Wee1 rather than Plk1. In addition, AZD1775 treatment accelerated mitosis onset overriding the DNA replication checkpoint and hastened Plk1-dependent phosphorylation. On the contrary selective Plk1 inhibition exerted opposite effects. Thus, at therapeutic concentrations, AZD1775 inhibited Wee1 rather than Plk1. This information will help to better interpret results obtained by using AZD1775 both in the clinical and experimental settings and provide a stronger rationale for combination therapies

Biology of the Mi-2/NuRD Complex in SLAC (Stemness, Longevity/Ageing, and Cancer)

The dynamic chromatin activities of Mi-2/Nucleosome Remodeling and Histone deacetylation (Mi-2/NuRD) complexes in mammals are at the basis of current research on stemness, longevity/ageing, and cancer (4-2-1/SLAC), and have been widely studied over the past decade in mammals and the elegant model organism, Caenorhabditis elegans. Interestingly, a common emergent theme from these studies is that of distinct coregulator-recruited Mi-2/NuRD complexes largely orchestrating the 4-2-1/SLAC within a unique paradigm by maintaining genome stability via DNA repair and controlling three types of transcriptional programs in concert in a number of cellular, tissue, and organism contexts. Thus, the core Mi-2/NuRD complex plays a central role in 4-2-1/SLAC. The plasticity and robustness of 4-2-1/SLAC can be interpreted as modulation of specific coregulator(s) within cell-specific, tissue-specific, stage-specific, or organism-specific niches during stress induction, ie, a functional module and its networking, thereby conferring differential responses to different environmental cues. According to “Occam’s razor”, a simple theory is preferable to a complex one, so this simplified notion might be useful for exploring 4-2-1/SLAC with a holistic view. This thought could also be valuable in forming strategies for future research, and could open up avenues for cancer prevention and antiageing strategies

Prevalence of Salmonella enterica and Listeria monocytogenes contamination in foods of animal origin in Italy.

The present survey collected and analyzed the results of routine testing for Salmonella enterica and Listeria monocytogenes on foods of animal origin submitted for official controls in Italy during 2001 to 2002. Salmonella was detected in 2.2% of 71,643 food samples examined, and the isolation rates ranged from 9.9% for raw poultry meat to less than 0.1% for dairy products. Isolation rates were also high in raw pork (4.9%) and processed meats (5.3%), which often involved pork. Low rates were observed in seafood (0.5%) and in ready-to-eat foods, such as grocery products (0.7%) and ice creams (0.1%). Serotyping showed that approximately 50% of the isolates belonged to the serotypes most commonly isolated from humans in Italy, thus confirming that most cases of human salmonellosis have a foodborne origin. Levels of L. monocytogenes were higher than what is accepted by the current regulation in 2.4% of 42,300 food samples. The positivity rates ranged from 10.3% in raw pork to none in eggs and egg products. Contamination rates were higher in other meat products (between 2 and 5%) and fish (6.5%) than in cheeses (1.1%) and other dairy products (0.6%). Routine control activities on the microbial contamination of foods can generate data with statistical and epidemiological value. Such data can be used as a basis for estimating the exposure of consumers to foodborne pathogens, following the trends of contamination over time, and evaluating the effects of control measures on the contamination of food

Association between plasma omentin-1 levels in type 2 diabetic patients and peripheral artery disease.

BACKGROUND: Type-2 diabetes mellitus is one of the major risk factors of atherosclerosis, particularly in peripheral artery disease (PAD). Several studies have documented a correlation between omentin-1 serum levels, atherosclerosis, and cardiovascular diseases. However, a clear link between circulating omentin-1 and PAD in diabetic patients has yet to be established. The aim of this study was to investigate the potential role of omentin-1 in PAD in type-2 diabetic patients. METHODS: In this cross-sectional study, we analyzed omentin-1 serum levels by ELISA in 600 type-2 diabetic patients with (n = 300) and without (n = 300) PAD at Fontaine's stage II, III, or IV. RESULTS: We found that omentin-1 serum levels were significantly lower in diabetic patients with PAD than in diabetic controls (29.46 vs 49.24 ng/mL, P < 0.001) and that the levels gradually decreased in proportion to disease severity (P < 0.05). The association between omentin-1 levels and PAD remained significant after adjusting for major risk factors in a multivariate analysis. CONCLUSIONS: Our results suggest that omentin-1 is reduced in type 2 diabetic patients with PAD and that omentin-1 levels are related to disease severity

Lrf suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion

Lrf has been previously described as a powerful proto-oncogene. Here we surprisingly demonstrate that Lrf plays a critical oncosuppressive role in the prostate. Prostate specific inactivation of Lrf leads to a dramatic acceleration of Pten-loss-driven prostate tumorigenesis through a bypass of Pten-loss-induced senescence (PICS). We show that LRF physically interacts with and functionally antagonizes SOX9 transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long non-coding RNA precursor for an Rb-targeting miRNA. Inactivation of Lrf in vivo leads to Rb down-regulation, PICS bypass and invasive prostate cancer. Importantly, we found that LRF is genetically lost, as well as down-regulated at both the mRNA and protein levels in a subset of human advanced prostate cancers. Thus, we identify LRF as a context-dependent cancer gene that can act as an oncogene in some contexts but also displays oncosuppressive-like activity in Pten−/− tumors

Comparative Analysis of Prothrombin Complex Concentrate and Fresh Frozen Plasma in the Management of Perioperative Bleeding after Coronary Artery Bypass Grafting

Background and Aim: Recent studies suggested that prothrombin complex concentrate (PCC) might be more effective than fresh frozen plasma (FFP) to reduce red blood cell (RBC) transfusion requirement after cardiac surgery. The benefits and risks associated with the use of PCC over FFP have been investigated in this study including patients undergoing isolated coronary artery bypass grafting(CABG) from a prospective, multicenter registry. Methods: This is a comparative analysis of 416 patients who received postoperatively FFP and 119 patients who received PCC with or without FFP after isolated CABG. Results: Mixed-effects regression analyses adjusted for multiple covariates and participating centers showed that PCC significantly decreased RBC transfusion (67.2% vs. 87.5%, adjusted OR 0.319, 95%CI 0.136-0.752) and platelet transfusion requirements (11.8% vs. 45.2%, adjusted OR 0.238, 95%CI 0.097-0.566) compared with FFP. The PCC cohort received a mean of 2.7\ub13.7 (median, 2.0, IQR 4) units of RBC and the FFP cohort received a mean of 4.9\ub16.3 (median, 3.0, IQR 4) units of RBC (adjusted coefficient, -1.926, 95%CI -3.357-0.494). The use of PCC increased the risk of KDIGO acute kidney injury (41.4% vs. 28.2%, adjusted OR 2.300, 1.203-4.400), but not of KDIGO acute kidney injury stage 3 (6.0% vs. 8.0%, OR 0.850, 95%CI 0.258-2.796) when compared with the FFP cohort. Conclusions: These results suggest that the use of PCC compared with FFP may reduce the need of blood transfusion after CABG. In view of the observational nature of this study, these results shoul