Abstract-Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. Recently, we have found that microRNA (miRNA) miR-145 is the most abundant miRNA in normal vascular walls and in freshly isolated VSMCs; however, the role of miR-145 in VSMC phenotypic modulation and vascular diseases is currently unknown. Here we find that miR-145 is selectively expressed in VSMCs of the vascular wall and its expression is significantly downregulated in the vascular walls with neointimal lesion formation and in cultured dedifferentiated VSMCs.

Several recent reports have suggested that microRNAs (miRNAs) might play critical roles in acute myocardial infarction (AMI). However, the miRNA expression signature in the early phase of AMI has not been identified. In this study, the miRNA expression signature was investigated in rat hearts 6 h after AMI. Compared with the expression signature in the noninfarcted areas, 38 miRNAs were differentially expressed in infarcted areas and 33 miRNAs were aberrantly expressed in the border areas. Remarkably, miR-21 expression was significantly down-regulated in infarcted areas, but was up-regulated in border areas. The down-regulation of miR-21 in the infarcted areas was inhibited by ischemic preconditioning, a known cardiac protective method. Overexpression of miR-21 via adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. Using both gain-of-function and loss-offunction approaches in cultured cardiac myocytes, we identified that miR-21 had a protective effect on ischemia-induced cell apoptosis that was associated with its target gene programmed cell death 4 and activator protein 1 pathway. The protective effect of miR-21 against ischemia-induced cardiac myocyte damage was further confirmed in vivo by decreased cell apoptosis in the border and infarcted areas of the infarcted rat hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as miR-21 may play critical roles in the early phase of AMI. MicroRNAs (miRNAs)3 are endogenous, noncoding, singlestranded RNAs of ϳ22 nucleotides and constitute a novel class of gene regulators (1-3). Analogous to the first RNA revolution in the 1980s, when Zaug and Cech (4) discovered the enzymatic activity of RNA, the more recent discoveries of RNA interference and miRNA may represent the second RNA revolution (5).Although the first miRNA, lin-4, was discovered in 1993 (6, 7), their presence in vertebrates was confirmed only in 2001 (8). miRNAs are initially transcribed in the nucleus by RNA polymerase II or III to form large pri-miRNA transcripts (9). These pri-miRNAs are then processed by the RNase III enzymes, Drosha, Pasha, and Dicer, to generate 18-to 24-nucleotide mature miRNAs. In addition to this miRNA biogenesis pathway, some miRNA precursors are able to bypass Drosha processing to produce miRNAs via Dicer, possibly representing an alternative pathway for miRNA biogenesis (10, 11). The mature miRNAs bind to the 3Ј-untranslated region of their mRNA targets and negatively regulate gene expression via degradation or translational inhibition.Currently, about 600 miRNAs have been cloned and sequenced in humans, and the estimated number of miRNA genes is as high as 1,000 in the human genome (12, 13). Functionally, an individual miRNA is as important as a transcription factor because it is able to regulate the expression of its multiple target genes. As a group, miRNAs are estimated to regulate over 30% of the genes in a cell (14). It is thus not surprising th...

IMPORTANCE An intraoperative higher level of positive end-expiratory positive pressure (PEEP) with alveolar recruitment maneuvers improves respiratory function in obese patients undergoing surgery, but the effect on clinical outcomes is uncertain. OBJECTIVE To determine whether a higher level of PEEP with alveolar recruitment maneuvers decreases postoperative pulmonary complications in obese patients undergoing surgery compared with a lower level of PEEP. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 2013 adults with body mass indices of 35 or greater and substantial risk for postoperative pulmonary complications who were undergoing noncardiac, nonneurological surgery under general anesthesia. The trial was conducted at 77 sites in 23 countries from July 2014-February 2018; final follow-up: May 2018. INTERVENTIONS Patients were randomized to the high level of PEEP group (n = 989), consisting of a PEEP level of 12 cm H 2 O with alveolar recruitment maneuvers (a stepwise increase of tidal volume and eventually PEEP) or to the low level of PEEP group (n = 987), consisting of a PEEP level of 4 cm H 2 O. All patients received volume-controlled ventilation with a tidal volume of 7 mL/kg of predicted body weight. MAIN OUTCOMES AND MEASURES The primary outcome was a composite of pulmonary complications within the first 5 postoperative days, including respiratory failure, acute respiratory distress syndrome, bronchospasm, new pulmonary infiltrates, pulmonary infection, aspiration pneumonitis, pleural effusion, atelectasis, cardiopulmonary edema, and pneumothorax. Among the 9 prespecified secondary outcomes, 3 were intraoperative complications, including hypoxemia (oxygen desaturation with SpO 2 Յ92% for >1 minute). RESULTS Among 2013 adults who were randomized, 1976 (98.2%) completed the trial (mean age, 48.8 years; 1381 [69.9%] women; 1778 [90.1%] underwent abdominal operations). In the intention-to-treat analysis, the primary outcome occurred in 211 of 989 patients (21.3%) in the high level of PEEP group compared with 233 of 987 patients (23.6%) in the low level of PEEP group (difference, −2.3% [95% CI, −5.9% to 1.4%]; risk ratio, 0.93 [95% CI, 0.83 to 1.04]; P = .23). Among the 9 prespecified secondary outcomes, 6 were not significantly different between the high and low level of PEEP groups, and 3 were significantly different, including fewer patients with hypoxemia (5.0% in the high level of PEEP group vs 13.6% in the low level of PEEP group; difference, −8.6% [95% CI, −11.1% to 6.1%]; P < .001). CONCLUSIONS AND RELEVANCE Among obese patients undergoing surgery under general anesthesia, an intraoperative mechanical ventilation strategy with a higher level of PEEP and alveolar recruitment maneuvers, compared with a strategy with a lower level of PEEP, did not reduce postoperative pulmonary complications.

ObjectiveThe authors describe their experience with left ventricular assist-device (LVAD) recipients undergoing noncardiac surgery and delineate surgical, anesthetic, and logistic factors important in the successful intraoperative management of these patients. Summary Background DataLeft ventricular assist-devices have become part of the armamentarium in the treatment of endstage heart failure. As the numbers of patients chronically supported with long-term implantable devices grows, general surgical problems that are commonly seen in other hospitalized patients are becoming manifest. Of particular interest is the intraoperative management of patients undergoing elective noncardiac surgical procedures. MethodsThe anesthesia records and clinical charts were reviewed for eight ventricular assist-device recipients undergoing general surgical procedures between August 1, 1990 and August 31, 1994. ResultsA total of 12 procedures were performed in 6 men and 2 women averaging 52.7 years of age. Mean time elapsed from device implantation to operation was 68 ± 35 days. Conventional inhalational and intravenous anesthetic techniques were well tolerated in these patients undergoing diverse surgical procedures. No perioperative mortality was observed. Five of eight patients went on to successful cardiac transplantation. ConclusionsHemodynamic recovery after LVAD insertion has defined a new group of patients who develop noncardiac surgical problems often seen in other critically ill patients. Recognition of the unique potential problems that the LVAD recipient may encounter in the perioperative period-in particular patient positioning, device limitations, and fluid and inotropic management-will ensure an optimal surgical outcome for LVAD recipients undergoing noncardiac surgery. 203

Comparing intraoperative strategies, ventilation with high PEEP resulted in increased production of inflammatory markers. Low PEEP resulted in lower levels of inflammatory markers. High Vt/low PEEP resulted in less histologic lung injury.